bims-nimamd Biomed News
on Neuroimmunity and neuroinflammation in ageing and metabolic disease
Issue of 2022‒11‒06
72 papers selected by
Fawaz Alzaïd
Sorbonne Université
  1. Identification of evolutionarily conserved regulators of muscle mitochondrial network organization.
  2. Parkin regulates adiposity by coordinating mitophagy with mitochondrial biogenesis in white adipocytes.
  3. Broken hierarchies.
  4. Transcriptional atlas of the human immune response to 13 vaccines reveals a common predictor of vaccine-induced antibody responses.
  5. Cooperative assembly of p97 complexes involved in replication termination.
  6. Immunosuppression.
  7. A double-negative thymocyte-specific enhancer augments Notch1 signaling to direct early T cell progenitor expansion, lineage restriction and β-selection.
  8. The epigenetic state of IL-4-polarized macrophages enables inflammatory cistromic expansion and extended synergistic response to TLR ligands.
  9. speedingCARs: accelerating the engineering of CAR T cells by signaling domain shuffling and single-cell sequencing.
  10. Understanding fibrosis pathogenesis via modeling macrophage-fibroblast interplay in immune-metabolic context.
  11. Mitochondrial DNA quality control in the female germline requires a unique programmed mitophagy.
  12. Cellular glycan modification by B3GAT1 broadly restricts influenza virus infection.
  13. A hierarchical transcription factor cascade regulates enteroendocrine cell diversity and plasticity in Drosophila.
  14. L-threonine promotes healthspan by expediting ferritin-dependent ferroptosis inhibition in C. elegans.
  15. Mitochondrial Fission Process 1 controls inner membrane integrity and protects against heart failure.
  16. Cap-dependent translation initiation monitored in living cells.
  17. Administration of broadly neutralizing anti-HIV-1 antibodies at ART initiation maintains long-term CD8+ T cell immunity.
  18. The contribution of common and rare genetic variants to variation in metabolic traits in 288,137 East Asians.
  19. MIR retrotransposons link the epigenome and the transcriptome of coding genes in acute myeloid leukemia.
  20. Tyrosine phosphorylation regulates RIPK1 activity to limit cell death and inflammation.
  21. CD8+ T cell differentiation status correlates with the feasibility of sustained unresponsiveness following oral immunotherapy.
  22. Integration of Hi-C with short and long-read genome sequencing reveals the structure of germline rearranged genomes.
  23. IER3IP1 is critical for maintaining glucose homeostasis through regulating the endoplasmic reticulum function and survival of β cells.
  24. Multifactorial profiling of epigenetic landscapes at single-cell resolution using MulTI-Tag.
  25. Glutamyl-prolyl-tRNA synthetase 1 coordinates early endosomal anti-inflammatory AKT signaling.
  26. Tumor factors stimulate lysosomal degradation of tumor antigens and undermine their cross-presentation in lung cancer.
  27. Heterogeneous plasma cells and long-lived subsets in response to immunization, autoantigen and microbiota.
  28. Nuclear corepressors NCOR1/NCOR2 regulate B cell development, maintain genomic integrity and prevent transformation.
  29. G307S DNAM-1 Mutation Exacerbates Autoimmune Encephalomyelitis via Enhancing CD4+ T Cell Activation.
  30. Mitochondrial signal transduction.
  31. Reactive astrocytes transduce inflammation in a blood-brain barrier model through a TNF-STAT3 signaling axis and secretion of alpha 1-antichymotrypsin.
  32. Arid1a loss potentiates pancreatic β-cell regeneration through activation of EGF signaling.
  33. Pan-vaccine analysis reveals innate immune endotypes predictive of antibody responses to vaccination.
  34. Gut microbiome dysbiosis in antibiotic-treated COVID-19 patients is associated with microbial translocation and bacteremia.
  35. Multi-ancestry genome-wide association analyses identify novel genetic mechanisms in rheumatoid arthritis.
  36. Metabolite annotation from knowns to unknowns through knowledge-guided multi-layer metabolic networking.
  37. A genetically encoded fluorescent biosensor for detecting itaconate with subcellular resolution in living macrophages.
  38. Audio long read: The controversial embryo tests that promise a better baby.
  39. Enhancer decommissioning by MLL4 ablation elicits dsRNA-interferon signaling and GSDMD-mediated pyroptosis to potentiate anti-tumor immunity.
  40. Phosphorylation of 17β-hydroxysteroid dehydrogenase 13 at serine 33 attenuates nonalcoholic fatty liver disease in mice.
  41. Multiplexed high-throughput immune cell imaging reveals molecular health-associated phenotypes.
  42. Gi/o protein-coupled receptor inhibition of beta-cell electrical excitability and insulin secretion depends on Na+/K+ ATPase activation.
  43. Pathogenesis of Cardiomyopathy Caused by Variants in ALPK3, an Essential Pseudokinase in the Cardiomyocyte Nucleus and Sarcomere.
  44. Multiphase coalescence mediates Hippo pathway activation.
  45. Plasma membrane flipping of Syntaxin-2 regulates its inhibitory action on insulin granule exocytosis.
  46. Melanocortin-4 receptors activate sympathetic preganglionic neurons and elevate blood pressure via TRPV1.
  47. Blocking PD-L1-PD-1 improves senescence surveillance and ageing phenotypes.
  48. Tempo: an unsupervised Bayesian algorithm for circadian phase inference in single-cell transcriptomics.
  49. BRD9-containing non-canonical BAF complex maintains somatic cell transcriptome and acts as a barrier to human reprogramming.
  50. Neuropeptide regulation of non-redundant ILC2 responses at barrier surfaces.
  51. Sexually dimorphic estrogen sensing in skeletal stem cells controls skeletal regeneration.
  52. Inulin fibre promotes microbiota-derived bile acids and type 2 inflammation.
  53. Lamin A/C-dependent chromatin architecture safeguards naïve pluripotency to prevent aberrant cardiovascular cell fate and function.
  54. Nociceptor neurons affect cancer immunosurveillance.
  55. MYC promotes immune-suppression in triple-negative breast cancer via inhibition of interferon signaling.
  56. Single-cell profiling reveals distinct adaptive immune hallmarks in MDA5+ dermatomyositis with therapeutic implications.
  57. Erratic and blood vessel-guided migration of astrocyte progenitors in the cerebral cortex.
  58. Disrupted β-cell-specific gene silencing causes congenital hyperinsulinism.
  59. Adipose tissue macrophages exert systemic metabolic control by manipulating local iron concentrations.
  60. A split, conditionally active mimetic of IL-2 reduces the toxicity of systemic cytokine therapy.
  61. Reversal of mitochondrial malate dehydrogenase 2 enables anaplerosis via redox rescue in respiration-deficient cells.
  62. V-ATPase/TORC1-mediated ATFS-1 translation directs mitochondrial UPR activation in C. elegans.
  63. 2'-5' oligoadenylate synthetase‑like 1 (OASL1) protects against atherosclerosis by maintaining endothelial nitric oxide synthase mRNA stability.
  64. Acute depletion of human core nucleoporin reveals direct roles in transcription control but dispensability for 3D genome organization.
  65. Prostaglandin PGE2 Receptor EP4 Regulates Microglial Phagocytosis and Increases Susceptibility to Diet-Induced Obesity.
  66. CMTM4 is required for IL-17A signaling.
  67. Inflammation fuels bone marrow exhaustion caused by Samd9l mutation.
  68. Use of a glycomics array to establish the anti-carbohydrate antibody repertoire in type 1 diabetes.
  69. Oxidized thioredoxin-1 restrains the NLRP1 inflammasome.
  70. Differential trafficking of ligands trogocytosed via CD28 versus CTLA4 promotes collective cellular control of co-stimulation.
  71. Tissue-wide genetic and cellular landscape shapes the execution of sequential PRC2 functions in neural stem cell lineage progression.
  72. Clonal lineage tracing reveals mechanisms skewing CD8+ T cell fate decisions in chronic infection.
  1. Nat Commun. 2022 Nov 04. 13(1): 6622
    Identification of evolutionarily conserved regulators of muscle mitochondrial network organization.
    Prasanna Katti, Peter T Ajayi, Angel Aponte, Christopher K E Bleck, Brian Glancy.
      Mitochondrial networks provide coordinated energy distribution throughout muscle cells. However, pathways specifying mitochondrial networks are incompletely understood and it is unclear how they might affect contractile fiber-type. Here, we show that natural energetic demands placed on Drosophila melanogaster muscles yield native cell-types among which contractile and mitochondrial network-types are regulated differentially. Proteomic analyses of indirect flight, jump, and leg muscles, together with muscles misexpressing known fiber-type specification factor salm, identified transcription factors H15 and cut as potential mitochondrial network regulators. We demonstrate H15 operates downstream of salm regulating flight muscle contractile and mitochondrial network-type. Conversely, H15 regulates mitochondrial network configuration but not contractile type in jump and leg muscles. Further, we find that cut regulates salm expression in flight muscles and mitochondrial network configuration in leg muscles. These data indicate cell type-specific regulation of muscle mitochondrial network organization through evolutionarily conserved transcription factors cut, salm, and H15.
    DOI:  https://doi.org/10.1038/s41467-022-34445-9
  2. Nat Commun. 2022 Nov 04. 13(1): 6661
    Parkin regulates adiposity by coordinating mitophagy with mitochondrial biogenesis in white adipocytes.
    Timothy M Moore, Lijing Cheng, Dane M Wolf, Jennifer Ngo, Mayuko Segawa, Xiaopeng Zhu, Alexander R Strumwasser, Yang Cao, Bethan L Clifford, Alice Ma, Philip Scumpia, Orian S Shirihai, Thomas Q de Aguiar Vallim, Markku Laakso, Aldons J Lusis, Andrea L Hevener, Zhenqi Zhou.
      Parkin, an E3 ubiquitin ligase, plays an essential role in mitochondrial quality control. However, the mechanisms by which Parkin connects mitochondrial homeostasis with cellular metabolism in adipose tissue remain unclear. Here, we demonstrate that Park2 gene (encodes Parkin) deletion specifically from adipose tissue protects mice against high-fat diet and aging-induced obesity. Despite a mild reduction in mitophagy, mitochondrial DNA content and mitochondrial function are increased in Park2 deficient white adipocytes. Moreover, Park2 gene deletion elevates mitochondrial biogenesis by increasing Pgc1α protein stability through mitochondrial superoxide-activated NAD(P)H quinone dehydrogenase 1 (Nqo1). Both in vitro and in vivo studies show that Nqo1 overexpression elevates Pgc1α protein level and mitochondrial DNA content and enhances mitochondrial activity in mouse and human adipocytes. Taken together, our findings indicate that Parkin regulates mitochondrial homeostasis by balancing mitophagy and Pgc1α-mediated mitochondrial biogenesis in white adipocytes, suggesting a potential therapeutic target in adipocytes to combat obesity and obesity-associated disorders.
    DOI:  https://doi.org/10.1038/s41467-022-34468-2
  3. Nat Immunol. 2022 Nov 04.
    Broken hierarchies.
    Ioana Visan.
      
    DOI:  https://doi.org/10.1038/s41590-022-01363-3
  4. Nat Immunol. 2022 Oct 31.
    Transcriptional atlas of the human immune response to 13 vaccines reveals a common predictor of vaccine-induced antibody responses.
    Human Immunology Project Consortium (HIPC)
      Systems vaccinology has defined molecular signatures and mechanisms of immunity to vaccination. However, comparative analysis of immunity to different vaccines is lacking. We integrated transcriptional data of over 3,000 samples, from 820 adults across 28 studies of 13 vaccines and analyzed vaccination-induced signatures of antibody responses. Most vaccines induced signatures of innate immunity and plasmablasts at days 1 and 7, respectively, after vaccination. However, the yellow fever vaccine induced an early transient signature of T and B cell activation at day 1, followed by delayed antiviral/interferon and plasmablast signatures that peaked at days 7 and 14-21, respectively. Thus, there was no evidence for a 'universal signature' that predicted antibody response to all vaccines. However, accounting for the asynchronous nature of responses, we defined a time-adjusted signature that predicted antibody responses across vaccines. These results provide a transcriptional atlas of immunity to vaccination and define a common, time-adjusted signature of antibody responses.
    DOI:  https://doi.org/10.1038/s41590-022-01328-6
  5. Nat Commun. 2022 Nov 03. 13(1): 6591
    Cooperative assembly of p97 complexes involved in replication termination.
    Olga V Kochenova, Sirisha Mukkavalli, Malavika Raman, Johannes C Walter.
      The p97 ATPase extracts polyubiquitylated proteins from diverse cellular structures in preparation for destruction by the proteasome. p97 functions with Ufd1-Npl4 and a variety of UBA-UBX co-factors, but how p97 complexes assemble on ubiquitylated substrates is unclear. To address this, we investigated how p97 disassembles the CMG helicase after it is ubiquitylated during replication termination. We show that p97Ufd1-Npl4 recruitment to CMG requires the UBA-UBX protein Ubxn7, and conversely, stable Ubxn7 binding to CMG requires p97Ufd1-Npl4. This cooperative assembly involves interactions between Ubxn7, p97, Ufd1-Npl4, and ubiquitin. Another p97 co-factor, Faf1, partially compensates for the loss of Ubxn7. Surprisingly, p97Ufd1-Npl4-Ubxn7 and p97Ufd1-Npl4-Faf1 also assemble cooperatively on unanchored ubiquitin chains. We propose that cooperative and substrate-independent recognition of ubiquitin chains allows p97 to recognize an unlimited number of polyubiquitylated proteins while avoiding the formation of partial, inactive complexes.
    DOI:  https://doi.org/10.1038/s41467-022-34210-y
  6. Nat Immunol. 2022 Nov 04.
    Immunosuppression.
    Stephanie Houston.
      
    DOI:  https://doi.org/10.1038/s41590-022-01362-4
  7. Nat Immunol. 2022 Oct 31.
    A double-negative thymocyte-specific enhancer augments Notch1 signaling to direct early T cell progenitor expansion, lineage restriction and β-selection.
    Mariko Kashiwagi, Daniela Salgado Figueroa, Ferhat Ay, Bruce A Morgan, Katia Georgopoulos.
      T cell differentiation requires Notch1 signaling. In the present study, we show that an enhancer upstream of Notch1 active in double-negative (DN) mouse thymocytes is responsible for raising Notch1 signaling intrathymically. This enhancer is required to expand multipotent progenitors intrathymically while delaying early differentiation until lineage restrictions have been established. Early thymic progenitors lacking the enhancer show accelerated differentiation through the DN stages and increased frequency of B, innate lymphoid (IL) and natural killer (NK) cell differentiation. Transcription regulators for T cell lineage restriction and commitment are expressed normally, but IL and NK cell gene expression persists after T cell lineage commitment and T cell receptor β VDJ recombination, Cd3 expression and β-selection have been impaired. This Notch1 enhancer is inactive in double-positive (DP) thymocytes. Its aberrant reactivation at this stage in Ikaros mutants is required for leukemogenesis. Thus, the DN-specific Notch1 enhancer harnesses the regulatory architecture of DN and DP thymocytes to achieve carefully orchestrated changes in Notch1 signaling required for early lineage restrictions and normal T cell differentiation.
    DOI:  https://doi.org/10.1038/s41590-022-01322-y
  8. Immunity. 2022 Oct 26. pii: S1074-7613(22)00545-3. [Epub ahead of print]
    The epigenetic state of IL-4-polarized macrophages enables inflammatory cistromic expansion and extended synergistic response to TLR ligands.
    Zsolt Czimmerer, Laszlo Halasz, Bence Daniel, Zsofia Varga, Krisztian Bene, Apolka Domokos, Marten Hoeksema, Zeyang Shen, Wilhelm K Berger, Timea Cseh, Karoly Jambrovics, Zsuzsanna Kolostyak, Ferenc Fenyvesi, Judit Varadi, Szilard Poliska, Gyorgy Hajas, Istvan Szatmari, Christopher K Glass, Attila Bacsi, Laszlo Nagy.
      Prior exposure to microenvironmental signals could fundamentally change the response of macrophages to subsequent stimuli. It is believed that T helper-2 (Th2)-cell-type cytokine interleukin-4 (IL-4) and Toll-like receptor (TLR) ligand-activated transcriptional programs mutually antagonize each other, and no remarkable convergence has been identified between them. In contrast, here, we show that IL-4-polarized macrophages established a hyperinflammatory gene expression program upon lipopolysaccharide (LPS) exposure. This phenomenon, which we termed extended synergy, was supported by IL-4-directed epigenomic remodeling, LPS-activated NF-κB-p65 cistrome expansion, and increased enhancer activity. The EGR2 transcription factor contributed to the extended synergy in a macrophage-subtype-specific manner. Consequently, the previously alternatively polarized macrophages produced increased amounts of immune-modulatory factors both in vitro and in vivo in a murine Th2 cell-type airway inflammation model upon LPS exposure. Our findings establish that IL-4-induced epigenetic reprogramming is responsible for the development of inflammatory hyperresponsiveness to TLR activation and contributes to lung pathologies.
    Keywords:  EGR2; IL-4; LPS; STAT6; Th2-type airway inflammation; epigenetic reprogramming; inflammation; macrophage; synergistic gene activation
    DOI:  https://doi.org/10.1016/j.immuni.2022.10.004
  9. Nat Commun. 2022 Nov 02. 13(1): 6555
    speedingCARs: accelerating the engineering of CAR T cells by signaling domain shuffling and single-cell sequencing.
    Rocío Castellanos-Rueda, Raphaël B Di Roberto, Florian Bieberich, Fabrice S Schlatter, Darya Palianina, Oanh T P Nguyen, Edo Kapetanovic, Heinz Läubli, Andreas Hierlemann, Nina Khanna, Sai T Reddy.
      Chimeric antigen receptors (CARs) consist of an antigen-binding region fused to intracellular signaling domains, enabling customized T cell responses against targets. Despite their major role in T cell activation, effector function and persistence, only a small set of immune signaling domains have been explored. Here we present speedingCARs, an integrated method for engineering CAR T cells via signaling domain shuffling and pooled functional screening. Leveraging the inherent modularity of natural signaling domains, we generate a library of 180 unique CAR variants genomically integrated into primary human T cells by CRISPR-Cas9. In vitro tumor cell co-culture, followed by single-cell RNA sequencing (scRNA-seq) and single-cell CAR sequencing (scCAR-seq), enables high-throughput screening for identifying several variants with tumor killing properties and T cell phenotypes markedly different from standard CARs. Mapping of the CAR scRNA-seq data onto that of tumor infiltrating lymphocytes further helps guide the selection of variants. These results thus help expand the CAR signaling domain combination space, and supports speedingCARs as a tool for the engineering of CARs for potential therapeutic development.
    DOI:  https://doi.org/10.1038/s41467-022-34141-8
  10. Nat Commun. 2022 Oct 30. 13(1): 6499
    Understanding fibrosis pathogenesis via modeling macrophage-fibroblast interplay in immune-metabolic context.
    Elisa Setten, Alessandra Castagna, Josué Manik Nava-Sedeño, Jonathan Weber, Roberta Carriero, Andreas Reppas, Valery Volk, Jessica Schmitz, Wilfried Gwinner, Haralampos Hatzikirou, Friedrich Feuerhake, Massimo Locati.
      Fibrosis is a progressive biological condition, leading to organ dysfunction in various clinical settings. Although fibroblasts and macrophages are known as key cellular players for fibrosis development, a comprehensive functional model that considers their interaction in the metabolic/immunologic context of fibrotic tissue has not been set up. Here we show, by transcriptome-based mathematical modeling in an in vitro system that represents macrophage-fibroblast interplay and reflects the functional effects of inflammation, hypoxia and the adaptive immune context, that irreversible fibrosis development is associated with specific combinations of metabolic and inflammatory cues. The in vitro signatures are in good alignment with transcriptomic profiles generated on laser captured glomeruli and cortical tubule-interstitial area, isolated from human transplanted kidneys with advanced stages of glomerulosclerosis and interstitial fibrosis/tubular atrophy, two clinically relevant conditions associated with organ failure in renal allografts. The model we describe here is validated on tissue based quantitative immune-phenotyping of biopsies from transplanted kidneys, demonstrating its feasibility. We conclude that the combination of in vitro and in silico modeling represents a powerful systems medicine approach to dissect fibrosis pathogenesis, applicable to specific pathological conditions, and develop coordinated targeted approaches.
    DOI:  https://doi.org/10.1038/s41467-022-34241-5
  11. Cell Metab. 2022 Nov 01. pii: S1550-4131(22)00456-9. [Epub ahead of print]34(11): 1809-1823.e6
    Mitochondrial DNA quality control in the female germline requires a unique programmed mitophagy.
    Jonathan M Palozzi, Swathi P Jeedigunta, Anastasia V Minenkova, Vernon L Monteiro, Zoe S Thompson, Toby Lieber, Thomas R Hurd.
      Mitochondria have their own DNA (mtDNA), which is susceptible to the accumulation of disease-causing mutations. To prevent deleterious mutations from being inherited, the female germline has evolved a conserved quality control mechanism that remains poorly understood. Here, through a large-scale screen, we uncover a unique programmed germline mitophagy (PGM) that is essential for mtDNA quality control. We find that PGM is developmentally triggered as germ cells enter meiosis by inhibition of the target of rapamycin complex 1 (TORC1). We identify a role for the RNA-binding protein Ataxin-2 (Atx2) in coordinating the timing of PGM with meiosis. We show that PGM requires the mitophagy receptor BNIP3, mitochondrial fission and translation factors, and members of the Atg1 complex, but not the mitophagy factors PINK1 and Parkin. Additionally, we report several factors that are critical for germline mtDNA quality control and show that pharmacological manipulation of one of these factors promotes mtDNA quality control.
    Keywords:  autophagy; germ line; germline; mitochondria; mitochondrial DNA; mitophagy; mtDNA; purifying selection; quality control
    DOI:  https://doi.org/10.1016/j.cmet.2022.10.005
  12. Nat Commun. 2022 Oct 29. 13(1): 6456
    Cellular glycan modification by B3GAT1 broadly restricts influenza virus infection.
    Joseph D Trimarco, Sarah L Nelson, Ryan R Chaparian, Alexandra I Wells, Nathan B Murray, Parastoo Azadi, Carolyn B Coyne, Nicholas S Heaton.
      Communicable respiratory viral infections pose both epidemic and pandemic threats and broad-spectrum antiviral strategies could improve preparedness for these events. To discover host antiviral restriction factors that may act as suitable targets for the development of host-directed antiviral therapies, we here conduct a whole-genome CRISPR activation screen with influenza B virus (IBV). A top hit from our screen, beta-1,3-glucuronyltransferase 1 (B3GAT1), effectively blocks IBV infection. Subsequent studies reveal that B3GAT1 activity prevents cell surface sialic acid expression. Due to this mechanism of action, B3GAT1 expression broadly restricts infection with viruses that require sialic acid for entry, including Victoria and Yamagata lineage IBVs, H1N1/H3N2 influenza A viruses (IAVs), and the unrelated enterovirus D68. To understand the potential utility of B3GAT1 induction as an antiviral strategy in vivo, we specifically express B3GAT1 in the murine respiratory epithelium and find that overexpression is not only well-tolerated, but also protects female mice from a lethal viral challenge with multiple influenza viruses, including a pandemic-like H1N1 IAV. Thus, B3GAT1 may represent a host-directed broad-spectrum antiviral target with utility against clinically relevant respiratory viruses.
    DOI:  https://doi.org/10.1038/s41467-022-34111-0
  13. Nat Commun. 2022 Oct 31. 13(1): 6525
    A hierarchical transcription factor cascade regulates enteroendocrine cell diversity and plasticity in Drosophila.
    Xingting Guo, Yongchao Zhang, Huanwei Huang, Rongwen Xi.
      Enteroendocrine cells (EEs) represent a heterogeneous cell population in intestine and exert endocrine functions by secreting a diverse array of neuropeptides. Although many transcription factors (TFs) required for specification of EEs have been identified in both mammals and Drosophila, it is not understood how these TFs work together to generate this considerable subtype diversity. Here we show that EE diversity in adult Drosophila is generated via an "additive hierarchical TF cascade". Specifically, a combination of a master TF, a secondary-level TF and a tertiary-level TF constitute a "TF code" for generating EE diversity. We also discover a high degree of post-specification plasticity of EEs, as changes in the code-including as few as one distinct TF-allow efficient switching of subtype identities. Our study thus reveals a hierarchically-organized TF code that underlies EE diversity and plasticity in Drosophila, which can guide investigations of EEs in mammals and inform their application in medicine.
    DOI:  https://doi.org/10.1038/s41467-022-34270-0
  14. Nat Commun. 2022 Nov 02. 13(1): 6554
    L-threonine promotes healthspan by expediting ferritin-dependent ferroptosis inhibition in C. elegans.
    Juewon Kim, Yunju Jo, Donghyun Cho, Dongryeol Ryu.
      The pathways that impact longevity in the wake of dietary restriction (DR) remain still ill-defined. Most studies have focused on nutrient limitation and perturbations of energy metabolism. We showed that the L-threonine was elevated in Caenorhabditis elegans under DR, and that L-threonine supplementation increased its healthspan. Using metabolic and transcriptomic profiling in worms that were fed with RNAi to induce loss of key candidate mediators. L-threonine supplementation and loss-of-threonine dehydrogenaseincreased the healthspan by attenuating ferroptosis in a ferritin-dependent manner. Transcriptomic analysis showed that FTN-1 encoding ferritin was elevated, implying FTN-1 is an essential mediator of longevity promotion. Organismal ferritin levels were positively correlated with chronological aging and L-threonine supplementation protected against age-associated ferroptosis through the DAF-16 and HSF-1 pathways. Our investigation uncovered the role of a distinct and universal metabolite, L-threonine, in DR-mediated improvement in organismal healthspan, suggesting it could be an effective intervention for preventing senescence progression and age-induced ferroptosis.
    DOI:  https://doi.org/10.1038/s41467-022-34265-x
  15. Nat Commun. 2022 Nov 04. 13(1): 6634
    Mitochondrial Fission Process 1 controls inner membrane integrity and protects against heart failure.
    Erminia Donnarumma, Michael Kohlhaas, Elodie Vimont, Etienne Kornobis, Thibault Chaze, Quentin Giai Gianetto, Mariette Matondo, Maryse Moya-Nilges, Christoph Maack, Timothy Wai.
      Mitochondria are paramount to the metabolism and survival of cardiomyocytes. Here we show that Mitochondrial Fission Process 1 (MTFP1) is an inner mitochondrial membrane (IMM) protein that is dispensable for mitochondrial division yet essential for cardiac structure and function. Constitutive knockout of cardiomyocyte MTFP1 in mice resulted in a fatal, adult-onset dilated cardiomyopathy accompanied by extensive mitochondrial and cardiac remodeling during the transition to heart failure. Prior to the onset of disease, knockout cardiac mitochondria displayed specific IMM defects: futile proton leak dependent upon the adenine nucleotide translocase and an increased sensitivity to the opening of the mitochondrial permeability transition pore, with which MTFP1 physically and genetically interacts. Collectively, our data reveal new functions of MTFP1 in the control of bioenergetic efficiency and cell death sensitivity and define its importance in preventing pathogenic cardiac remodeling.
    DOI:  https://doi.org/10.1038/s41467-022-34316-3
  16. Nat Commun. 2022 Nov 02. 13(1): 6558
    Cap-dependent translation initiation monitored in living cells.
    Valentina Gandin, Brian P English, Melanie Freeman, Louis-Philippe Leroux, Stephan Preibisch, Deepika Walpita, Maritza Jaramillo, Robert H Singer.
      mRNA translation is tightly regulated to preserve cellular homeostasis. Despite extensive biochemical, genetic, and structural studies, a detailed understanding of mRNA translation regulation is lacking. Imaging methodologies able to resolve the binding dynamics of translation factors at single-cell and single-mRNA resolution were necessary to fully elucidate regulation of this paramount process. Here live-cell spectroscopy and single-particle tracking were combined to interrogate the binding dynamics of endogenous initiation factors to the 5'cap. The diffusion of initiation factors (IFs) changed markedly upon their association with mRNA. Quantifying their diffusion characteristics revealed the sequence of IFs assembly and disassembly in cell lines and the clustering of translation in neurons. This approach revealed translation regulation at high spatial and temporal resolution that can be applied to the formation of any endogenous complex that results in a measurable shift in diffusion.
    DOI:  https://doi.org/10.1038/s41467-022-34052-8
  17. Nat Commun. 2022 Oct 29. 13(1): 6473
    Administration of broadly neutralizing anti-HIV-1 antibodies at ART initiation maintains long-term CD8+ T cell immunity.
    Miriam Rosás-Umbert, Jesper D Gunst, Marie H Pahus, Rikke Olesen, Mariane Schleimann, Paul W Denton, Victor Ramos, Adam Ward, Natalie N Kinloch, Dennis C Copertino, Tuixent Escribà, Anuska Llano, Zabrina L Brumme, R Brad Jones, Beatriz Mothe, Christian Brander, Julie Fox, Michel C Nussenzweig, Sarah Fidler, Marina Caskey, Martin Tolstrup, Ole S Søgaard.
      In simian-human immunodeficiency virus (SHIV)-infected non-human primates, broadly neutralizing antibodies (bNAbs) against the virus appear to stimulate T cell immunity. To determine whether this phenomenon also occurs in humans we measured HIV-1-specific cellular immunity longitudinally in individuals with HIV-1 starting antiviral therapy (ART) with or without adjunctive bNAb 3BNC117 treatment. Using the activation-induced marker (AIM) assay and interferon-γ release, we observe that frequencies of Pol- and Gag-specific CD8+ T cells, as well as Gag-induced interferon-γ responses, are significantly higher among individuals that received adjunctive 3BNC117 compared to ART-alone at 3 and 12 months after starting ART. The observed changes in cellular immunity were directly correlated to pre-treatment 3BNC117-sensitivity. Notably, increased HIV-1-specific immunity is associated with partial or complete ART-free virologic control during treatment interruption for up to 4 years. Our findings suggest that bNAb treatment at the time of ART initiation maintains HIV-1-specific CD8+ T cell responses that are associated with ART-free virologic control.
    DOI:  https://doi.org/10.1038/s41467-022-34171-2
  18. Nat Commun. 2022 Nov 04. 13(1): 6642
    The contribution of common and rare genetic variants to variation in metabolic traits in 288,137 East Asians.
    Young Jin Kim, Sanghoon Moon, Mi Yeong Hwang, Sohee Han, Hye-Mi Jang, Jinhwa Kong, Dong Mun Shin, Kyungheon Yoon, Sung Min Kim, Jong-Eun Lee, Anubha Mahajan, Hyun-Young Park, Mark I McCarthy, Yoon Shin Cho, Bong-Jo Kim.
      Metabolic traits are heritable phenotypes widely-used in assessing the risk of various diseases. We conduct a genome-wide association analysis (GWAS) of nine metabolic traits (including glycemic, lipid, liver enzyme levels) in 125,872 Korean subjects genotyped with the Korea Biobank Array. Following meta-analysis with GWAS from Biobank Japan identify 144 novel signals (MAF ≥ 1%), of which 57.0% are replicated in UK Biobank. Additionally, we discover 66 rare (MAF < 1%) variants, 94.4% of them co-incident to common loci, adding to allelic series. Although rare variants have limited contribution to overall trait variance, these lead, in carriers, substantial loss of predictive accuracy from polygenic predictions of disease risk from common variant alone. We capture groups with up to 16-fold variation in type 2 diabetes (T2D) prevalence by integration of genetic risk scores of fasting plasma glucose and T2D and the I349F rare protective variant. This study highlights the need to consider the joint contribution of both common and rare variants on inherited risk of metabolic traits and related diseases.
    DOI:  https://doi.org/10.1038/s41467-022-34163-2
  19. Nat Commun. 2022 Oct 31. 13(1): 6524
    MIR retrotransposons link the epigenome and the transcriptome of coding genes in acute myeloid leukemia.
    Aristeidis G Telonis, Qin Yang, Hsuan-Ting Huang, Maria E Figueroa.
      DNMT3A and IDH1/2 mutations combinatorically regulate the transcriptome and the epigenome in acute myeloid leukemia; yet the mechanisms of this interplay are unknown. Using a systems approach within topologically associating domains, we find that genes with significant expression-methylation correlations are enriched in signaling and metabolic pathways. The common denominator across these methylation-regulated genes is the density in MIR retrotransposons of their introns. Moreover, a discrete number of CpGs overlapping enhancers are responsible for regulating most of these genes. Established mouse models recapitulate the dependency of MIR-rich genes on the balanced expression of epigenetic modifiers, while projection of leukemic profiles onto normal hematopoiesis ones further consolidates the dependencies of methylation-regulated genes on MIRs. Collectively, MIR elements on genes and enhancers are susceptible to changes in DNA methylation activity and explain the cooperativity of proteins in this pathway in normal and malignant hematopoiesis.
    DOI:  https://doi.org/10.1038/s41467-022-34211-x
  20. Nat Commun. 2022 Nov 03. 13(1): 6603
    Tyrosine phosphorylation regulates RIPK1 activity to limit cell death and inflammation.
    Hailin Tu, Weihang Xiong, Jie Zhang, Xueqiang Zhao, Xin Lin.
      Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) is a cytosolic protein kinase that regulates multiple inflammatory and cell death pathways. Serine/Threonine phosphorylation of RIPK1 is known to suppress RIPK1 kinase-mediated cell death in the contexts of inflammation, infection and embryogenesis, however, regulation by tyrosine phosphorylation has not been reported. Here, we show that non-receptor tyrosine kinases Janus kinase 1 (JAK1) and SRC are able to phosphorylate RIPK1 at Y384 (Y383 in murine RIPK1), leading to suppression of TNF-induced cell death. Mice bearing a homozygous Ripk1 mutation that prevents tyrosine phosphorylation of RIPK1 (Ripk1Y383F/Y383F), develop systemic inflammation and emergency haematopoiesis. Mechanistically, Ripk1Y383F/Y383F mutation promotes RIPK1 kinase activation and enhances TNF-induced apoptosis and necroptosis, which is partially due to impaired recruitment and activation of MAP kinase-activated protein kinase 2 (MK2). The systemic inflammation and emergency haematopoiesis in Ripk1Y383F/Y383F mice are largely alleviated by RIPK1 kinase inhibition, and prevented by genomic deletions targeted to the upstream pathway (either to Tumor necrosis factor receptor 1 or RIPK3 and Caspase8 simultaneously). In summary, our results demonstrate that tyrosine phosphorylation of RIPK1 is critical for regulating RIPK1 activity to limit cell death and inflammation.
    DOI:  https://doi.org/10.1038/s41467-022-34080-4
  21. Nat Commun. 2022 Nov 04. 13(1): 6646
    CD8+ T cell differentiation status correlates with the feasibility of sustained unresponsiveness following oral immunotherapy.
    Abhinav Kaushik, Diane Dunham, Xiaorui Han, Evan Do, Sandra Andorf, Sheena Gupta, Andrea Fernandes, Laurie Elizabeth Kost, Sayantani B Sindher, Wong Yu, Mindy Tsai, Robert Tibshirani, Scott D Boyd, Manisha Desai, Holden T Maecker, Stephen J Galli, R Sharon Chinthrajah, Rosemarie H DeKruyff, Monali Manohar, Kari C Nadeau.
      While food allergy oral immunotherapy (OIT) can provide safe and effective desensitization (DS), the immune mechanisms underlying development of sustained unresponsiveness (SU) following a period of avoidance are largely unknown. Here, we compare high dimensional phenotypes of innate and adaptive immune cell subsets of participants in a previously reported, phase 2 randomized, controlled, peanut OIT trial who achieved SU vs. DS (no vs. with allergic reactions upon food challenge after a withdrawal period; n = 21 vs. 30 respectively among total 120 intent-to-treat participants). Lower frequencies of naïve CD8+ T cells and terminally differentiated CD57+CD8+ T cell subsets at baseline (pre-OIT) are associated with SU. Frequency of naïve CD8+ T cells shows a significant positive correlation with peanut-specific and Ara h 2-specific IgE levels at baseline. Higher frequencies of IL-4+ and IFNγ+ CD4+ T cells post-OIT are negatively correlated with SU. Our findings provide evidence that an immune signature consisting of certain CD8+ T cell subset frequencies is potentially predictive of SU following OIT.
    DOI:  https://doi.org/10.1038/s41467-022-34222-8
  22. Nat Commun. 2022 Oct 29. 13(1): 6470
    Integration of Hi-C with short and long-read genome sequencing reveals the structure of germline rearranged genomes.
    Robert Schöpflin, Uirá Souto Melo, Hossein Moeinzadeh, David Heller, Verena Laupert, Jakob Hertzberg, Manuel Holtgrewe, Nico Alavi, Marius-Konstantin Klever, Julius Jungnitsch, Emel Comak, Seval Türkmen, Denise Horn, Yannis Duffourd, Laurence Faivre, Patrick Callier, Damien Sanlaville, Orsetta Zuffardi, Romano Tenconi, Nehir Edibe Kurtas, Sabrina Giglio, Bettina Prager, Anna Latos-Bielenska, Ida Vogel, Merete Bugge, Niels Tommerup, Malte Spielmann, Antonio Vitobello, Vera M Kalscheuer, Martin Vingron, Stefan Mundlos.
      Structural variants are a common cause of disease and contribute to a large extent to inter-individual variability, but their detection and interpretation remain a challenge. Here, we investigate 11 individuals with complex genomic rearrangements including germline chromothripsis by combining short- and long-read genome sequencing (GS) with Hi-C. Large-scale genomic rearrangements are identified in Hi-C interaction maps, allowing for an independent assessment of breakpoint calls derived from the GS methods, resulting in >300 genomic junctions. Based on a comprehensive breakpoint detection and Hi-C, we achieve a reconstruction of whole rearranged chromosomes. Integrating information on the three-dimensional organization of chromatin, we observe that breakpoints occur more frequently than expected in lamina-associated domains (LADs) and that a majority reshuffle topologically associating domains (TADs). By applying phased RNA-seq, we observe an enrichment of genes showing allelic imbalanced expression (AIG) within 100 kb around the breakpoints. Interestingly, the AIGs hit by a breakpoint (19/22) display both up- and downregulation, thereby suggesting different mechanisms at play, such as gene disruption and rearrangements of regulatory information. However, the majority of interpretable genes located 200 kb around a breakpoint do not show significant expression changes. Thus, there is an overall robustness in the genome towards large-scale chromosome rearrangements.
    DOI:  https://doi.org/10.1038/s41467-022-34053-7
  23. Proc Natl Acad Sci U S A. 2022 Nov 08. 119(45): e2204443119
    IER3IP1 is critical for maintaining glucose homeostasis through regulating the endoplasmic reticulum function and survival of β cells.
    Jing Yang, Jinyang Zhen, Wenli Feng, Zhenqian Fan, Li Ding, Xiaoyun Yang, Yumeng Huang, Hua Shu, Jing Xie, Xin Li, Jingting Qiao, Yuxin Fan, Jinhong Sun, Na Li, Tengli Liu, Shusen Wang, Xiaona Zhang, Peter Arvan, Ming Liu.
      Recessive mutations in IER3IP1 (immediate early response 3 interacting protein 1) cause a syndrome of microcephaly, epilepsy, and permanent neonatal diabetes (MEDS). IER3IP1 encodes an endoplasmic reticulum (ER) membrane protein, which is crucial for brain development; however, the role of IER3IP1 in β cells remains unknown. We have generated two mouse models with either constitutive or inducible IER3IP1 deletion in β cells, named IER3IP1-βKO and IER3IP1-iβKO, respectively. We found that IER3IP1-βKO causes severe early-onset, insulin-deficient diabetes. Functional studies revealed a markedly dilated β-cell ER along with increased proinsulin misfolding and elevated expression of the ER chaperones, including PDI, ERO1, BiP, and P58IPK. Islet transcriptome analysis confirmed by qRT-PCR revealed decreased expression of genes associated with β-cell maturation, cell cycle, and antiapoptotic genes, accompanied by increased expression of antiproliferation genes. Indeed, multiple independent approaches further demonstrated that IER3IP1-βKO impaired β-cell maturation and proliferation, along with increased condensation of β-cell nuclear chromatin. Inducible β-cell IER3IP1 deletion in adult (8-wk-old) mice induced a similar diabetic phenotype, suggesting that IER3IP1 is also critical for function and survival even after β-cell early development. Importantly, IER3IP1 was decreased in β cells of patients with type 2 diabetes (T2D), suggesting an association of IER3IP1 deficiency with β-cell dysfunction in the more-common form of diabetes. These data not only uncover a critical role of IER3IP1 in β cells but also provide insight into molecular basis of diabetes caused by IER3IP1 mutations.
    Keywords:  ER stress; IER3IP1; diabetes; β cell proliferation; β cell survival
    DOI:  https://doi.org/10.1073/pnas.2204443119
  24. Nat Biotechnol. 2022 Oct 31.
    Multifactorial profiling of epigenetic landscapes at single-cell resolution using MulTI-Tag.
    Michael P Meers, Geneva Llagas, Derek H Janssens, Christine A Codomo, Steven Henikoff.
      Chromatin profiling at locus resolution uncovers gene regulatory features that define cell types and developmental trajectories, but it remains challenging to map and compare different chromatin-associated proteins in the same sample. Here we describe Multiple Target Identification by Tagmentation (MulTI-Tag), an antibody barcoding approach for profiling multiple chromatin features simultaneously in single cells. We optimized MulTI-Tag to retain high sensitivity and specificity, and we demonstrate detection of up to three histone modifications in the same cell: H3K27me3, H3K4me1/2 and H3K36me3. We apply MulTI-Tag to resolve distinct cell types and developmental trajectories; to distinguish unique, coordinated patterns of active and repressive element regulatory usage associated with differentiation outcomes; and to uncover associations between histone marks. Multifactorial epigenetic profiling holds promise for comprehensively characterizing cell-specific gene regulatory landscapes in development and disease.
    DOI:  https://doi.org/10.1038/s41587-022-01522-9
  25. Nat Commun. 2022 Oct 29. 13(1): 6455
    Glutamyl-prolyl-tRNA synthetase 1 coordinates early endosomal anti-inflammatory AKT signaling.
    Eun-Young Lee, Su-Man Kim, Jung Hwan Hwang, Song Yee Jang, Shinhye Park, Sanghyeon Choi, Ga Seul Lee, Jungwon Hwang, Jeong Hee Moon, Paul L Fox, Sunghoon Kim, Chul-Ho Lee, Myung Hee Kim.
      The AKT signaling pathway plays critical roles in the resolution of inflammation. However, the underlying mechanisms of anti-inflammatory regulation and signal coordination remain unclear. Here, we report that anti-inflammatory AKT signaling is coordinated by glutamyl-prolyl-tRNA synthetase 1 (EPRS1). Upon inflammatory activation, AKT specifically phosphorylates Ser999 of EPRS1 in the cytoplasmic multi-tRNA synthetase complex, inducing release of EPRS1. EPRS1 compartmentalizes AKT to early endosomes via selective binding to the endosomal membrane lipid phosphatidylinositol 3-phosphate and assembles an AKT signaling complex specific for anti-inflammatory activity. These events promote AKT activation-mediated GSK3β phosphorylation, which increase anti-inflammatory cytokine production. EPRS1-deficient macrophages do not assemble the early endosomal complex and consequently exacerbate inflammation, decreasing the survival of EPRS1-deficient mice undergoing septic shock and ulcerative colitis. Collectively, our findings show that the housekeeping protein EPRS1 acts as a mediator of inflammatory homeostasis by coordinating compartment-specific AKT signaling.
    DOI:  https://doi.org/10.1038/s41467-022-34226-4
  26. Nat Commun. 2022 Nov 04. 13(1): 6623
    Tumor factors stimulate lysosomal degradation of tumor antigens and undermine their cross-presentation in lung cancer.
    Zhen Lu, Jinyun Chen, Pengfei Yu, Matthew J Atherton, Jun Gui, Vivek S Tomar, Justin D Middleton, Neil T Sullivan, Sunil Singhal, Subin S George, Ashley G Woolfork, Aalim M Weljie, Tsonwin Hai, Evgeniy B Eruslanov, Serge Y Fuchs.
      Activities of dendritic cells (DCs) that present tumor antigens are often suppressed in tumors. Here we report that this suppression is induced by tumor microenvironment-derived factors, which activate the activating transcription factor-3 (ATF3) transcription factor and downregulate cholesterol 25-hydroxylase (CH25H). Loss of CH25H in antigen presenting cells isolated from human lung tumors is associated with tumor growth and lung cancer progression. Accordingly, mice lacking CH25H in DCs exhibit an accelerated tumor growth, decreased infiltration and impaired activation of intratumoral CD8+ T cells. These mice do not establish measurable long-term immunity against malignant cells that undergo chemotherapy-induced immunogenic cell death. Mechanistically, downregulation of CH25H stimulates membrane fusion between endo-phagosomes and lysosomes, accelerates lysosomal degradation and restricts cross-presentation of tumor antigens in the intratumoral DCs. Administration of STING agonist MSA-2 reduces the lysosomal activity in DCs, restores antigen cross presentation, and increases therapeutic efficacy of PD-1 blockade against tumour challenge in a CH25H-dependent manner. These studies highlight the importance of downregulation of CH25H in DCs for tumor immune evasion and resistance to therapy.
    DOI:  https://doi.org/10.1038/s41467-022-34428-w
  27. Nat Immunol. 2022 Oct 31.
    Heterogeneous plasma cells and long-lived subsets in response to immunization, autoantigen and microbiota.
    Xin Liu, Jiacheng Yao, Yongshan Zhao, Jianbin Wang, Hai Qi.
      Durable antibody immunity depends on long-lived plasma cells (LLPCs) that primarily reside in the bone marrow (BM). However, due to LLPC rarity, it has not been possible to define their phenotypes or determine their heterogeneity. By single-cell mRNA sequencing, cytometry and a genetic pulse-chase mouse model, we show that IgG and IgM LLPCs display an EpCAMhiCXCR3- phenotype, whereas IgA LLPCs are Ly6AhiTigit-. While IgG and IgA LLPCs are mainly contributed by somatically hypermutated cells following immunization or infection, cells with innate properties and public antibodies are found in IgA and IgM LLPC compartments. Particularly, IgM LLPCs are highly enriched with public clones shared among different individual animals, differentiated in a T cell-independent manner and have affinity for self-antigens and microbial-derived antigens. Taken together, our work reveals different routes toward LLPC development and paves the way for deeper understanding of cellular and molecular underpinnings of long-term antibody immunity.
    DOI:  https://doi.org/10.1038/s41590-022-01345-5
  28. Nat Immunol. 2022 Oct 31.
    Nuclear corepressors NCOR1/NCOR2 regulate B cell development, maintain genomic integrity and prevent transformation.
    Robin D Lee, Todd P Knutson, Sarah A Munro, Jeffrey T Miller, Lynn M Heltemes-Harris, Charles G Mullighan, Kristen Jepsen, Michael A Farrar.
      The nuclear corepressors NCOR1 and NCOR2 interact with transcription factors involved in B cell development and potentially link these factors to alterations in chromatin structure and gene expression. Herein, we demonstrate that Ncor1/2 deletion limits B cell differentiation via impaired recombination, attenuates pre-BCR signaling and enhances STAT5-dependent transcription. Furthermore, NCOR1/2-deficient B cells exhibited derepression of EZH2-repressed gene modules, including the p53 pathway. These alterations resulted in aberrant Rag1 and Rag2 expression and accessibility. Whole-genome sequencing of Ncor1/2 DKO B cells identified increased number of structural variants with cryptic recombination signal sequences. Finally, deletion of Ncor1 alleles in mice facilitated leukemic transformation, whereas human leukemias with less NCOR1 correlated with worse survival. NCOR1/2 mutations in human leukemia correlated with increased RAG expression and number of structural variants. These studies illuminate how the corepressors NCOR1/2 regulate B cell differentiation and provide insights into how NCOR1/2 mutations may promote B cell transformation.
    DOI:  https://doi.org/10.1038/s41590-022-01343-7
  29. J Immunol. 2022 Nov 02. pii: ji2200608. [Epub ahead of print]
    G307S DNAM-1 Mutation Exacerbates Autoimmune Encephalomyelitis via Enhancing CD4+ T Cell Activation.
    Rikito Murata, Shota Kinoshita, Kenshiro Matsuda, Atsushi Kawaguchi, Akira Shibuya, Kazuko Shibuya.
      Although rs763361, which causes a nonsynonymous glycine-to-serine mutation at residue 307 (G307S mutation) of the DNAX accessory molecule-1 (DNAM-1) immunoreceptor, is a single-nucleotide polymorphism associated with autoimmune disease susceptibility, little is known about how the single-nucleotide polymorphism is involved in pathogenesis. In this study, we established human CD4+ T cell transfectants stably expressing wild-type (WT) or G307S DNAM-1 and showed that the costimulatory signal from G307S DNAM-1 induced greater proinflammatory cytokine production and cell proliferation than that from wild-type DNAM-1. The G307S mutation also enhanced the recruitment of the tyrosine kinase Lck and augmented p-Tyr322 of DNAM-1. We also established a mouse myelin Ag-specific CD4+ T cell transfectant stably expressing the chimeric DNAM-1 (chDNAM-1) consisting of the extracellular, transmembrane, and a part of intracellular regions of mouse DNAM-1 (residues 1-285) fused with the part of the intracellular region (residues 286-336) of human WT or G307S chDNAM-1. Adoptive transfer of the mouse T cell transfectant expressing the G307S chDNAM-1 into mice exacerbated experimental autoimmune encephalomyelitis compared with the transfer of cells expressing the WT chDNAM-1. These findings suggest that rs763361 is a gain-of-function mutation that enhances DNAM-1-mediated costimulatory signaling for proinflammatory responses.
    DOI:  https://doi.org/10.4049/jimmunol.2200608
  30. Cell Metab. 2022 Nov 01. pii: S1550-4131(22)00459-4. [Epub ahead of print]34(11): 1620-1653
    Mitochondrial signal transduction.
    Martin Picard, Orian S Shirihai.
      The analogy of mitochondria as powerhouses has expired. Mitochondria are living, dynamic, maternally inherited, energy-transforming, biosynthetic, and signaling organelles that actively transduce biological information. We argue that mitochondria are the processor of the cell, and together with the nucleus and other organelles they constitute the mitochondrial information processing system (MIPS). In a three-step process, mitochondria (1) sense and respond to both endogenous and environmental inputs through morphological and functional remodeling; (2) integrate information through dynamic, network-based physical interactions and diffusion mechanisms; and (3) produce output signals that tune the functions of other organelles and systemically regulate physiology. This input-to-output transformation allows mitochondria to transduce metabolic, biochemical, neuroendocrine, and other local or systemic signals that enhance organismal adaptation. An explicit focus on mitochondrial signal transduction emphasizes the role of communication in mitochondrial biology. This framework also opens new avenues to understand how mitochondria mediate inter-organ processes underlying human health.
    Keywords:  amplification; communication; energy; evolution; health; membrane potential; metabokines; mito-nuclear signaling; mitochondrial networks; mitokines; mitotypes; receptors; signal transduction; steroid hormones; stress responses; tissue-specific
    DOI:  https://doi.org/10.1016/j.cmet.2022.10.008
  31. Nat Commun. 2022 Nov 02. 13(1): 6581
    Reactive astrocytes transduce inflammation in a blood-brain barrier model through a TNF-STAT3 signaling axis and secretion of alpha 1-antichymotrypsin.
    Hyosung Kim, Kun Leng, Jinhee Park, Alexander G Sorets, Suil Kim, Alena Shostak, Rebecca J Embalabala, Kate Mlouk, Ketaki A Katdare, Indigo V L Rose, Sarah M Sturgeon, Emma H Neal, Yan Ao, Shinong Wang, Michael V Sofroniew, Jonathan M Brunger, Douglas G McMahon, Matthew S Schrag, Martin Kampmann, Ethan S Lippmann.
      Astrocytes are critical components of the neurovascular unit that support blood-brain barrier (BBB) function. Pathological transformation of astrocytes to reactive states can be protective or harmful to BBB function. Here, using a human induced pluripotent stem cell (iPSC)-derived BBB co-culture model, we show that tumor necrosis factor (TNF) transitions astrocytes to an inflammatory reactive state that causes BBB dysfunction through activation of STAT3 and increased expression of SERPINA3, which encodes alpha 1-antichymotrypsin (α1ACT). To contextualize these findings, we correlated astrocytic STAT3 activation to vascular inflammation in postmortem human tissue. Further, in murine brain organotypic cultures, astrocyte-specific silencing of Serpina3n reduced vascular inflammation after TNF challenge. Last, treatment with recombinant Serpina3n in both ex vivo explant cultures and in vivo was sufficient to induce BBB dysfunction-related molecular changes. Overall, our results define the TNF-STAT3-α1ACT signaling axis as a driver of an inflammatory reactive astrocyte signature that contributes to BBB dysfunction.
    DOI:  https://doi.org/10.1038/s41467-022-34412-4
  32. Cell Rep. 2022 Nov 01. pii: S2211-1247(22)01446-2. [Epub ahead of print]41(5): 111581
    Arid1a loss potentiates pancreatic β-cell regeneration through activation of EGF signaling.
    Cemre Celen, Jen-Chieh Chuang, Shunli Shen, Lin Li, Gianna Maggiore, Yuemeng Jia, Xin Luo, Austin Moore, Yunguan Wang, Jordan E Otto, Clayton K Collings, Zixi Wang, Xuxu Sun, Ibrahim Nassour, Jiyoung Park, Alexandra Ghaben, Tao Wang, Sam C Wang, Philipp E Scherer, Cigall Kadoch, Hao Zhu.
      The dynamic regulation of β-cell abundance is poorly understood. Since chromatin remodeling plays critical roles in liver regeneration, these mechanisms could be generally important for regeneration in other tissues. Here, we show that the ARID1A mammalian SWI/SNF complex subunit is a critical regulator of β-cell regeneration. Arid1a is highly expressed in quiescent β-cells but is physiologically suppressed when β-cells proliferate during pregnancy or after pancreas resection. Whole-body Arid1a knockout mice are protected against streptozotocin-induced diabetes. Cell-type and temporally specific genetic dissection show that β-cell-specific Arid1a deletion can potentiate β-cell regeneration in multiple contexts. Transcriptomic and epigenomic profiling of mutant islets reveal increased neuregulin-ERBB-NR4A signaling. Chemical inhibition of ERBB or NR4A1 blocks increased regeneration associated with Arid1a loss. Mammalian SWI/SNF (mSWI/SNF) complex activity is a barrier to β-cell regeneration in physiologic and disease states.
    Keywords:  Arid1a; CP: Cell biology; CP: Developmental biology; EGFR/ERBB; NR4A nuclear receptors; NRG/EGF signaling; SWI/SNF; chromatin remodeling; diabetes; islets; β-cell regeneration
    DOI:  https://doi.org/10.1016/j.celrep.2022.111581
  33. Nat Immunol. 2022 Oct 31.
    Pan-vaccine analysis reveals innate immune endotypes predictive of antibody responses to vaccination.
    Human Immunology Project Consortium (HIPC)
      Several studies have shown that the pre-vaccination immune state is associated with the antibody response to vaccination. However, the generalizability and mechanisms that underlie this association remain poorly defined. Here, we sought to identify a common pre-vaccination signature and mechanisms that could predict the immune response across 13 different vaccines. Analysis of blood transcriptional profiles across studies revealed three distinct pre-vaccination endotypes, characterized by the differential expression of genes associated with a pro-inflammatory response, cell proliferation, and metabolism alterations. Importantly, individuals whose pre-vaccination endotype was enriched in pro-inflammatory response genes known to be downstream of nuclear factor-kappa B showed significantly higher serum antibody responses 1 month after vaccination. This pro-inflammatory pre-vaccination endotype showed gene expression characteristic of the innate activation state triggered by Toll-like receptor ligands or adjuvants. These results demonstrate that wide variations in the transcriptional state of the immune system in humans can be a key determinant of responsiveness to vaccination.
    DOI:  https://doi.org/10.1038/s41590-022-01329-5
  34. Nat Commun. 2022 Nov 01. 13(1): 5926
    Gut microbiome dysbiosis in antibiotic-treated COVID-19 patients is associated with microbial translocation and bacteremia.
    Yale IMPACT Research Team
      Although microbial populations in the gut microbiome are associated with COVID-19 severity, a causal impact on patient health has not been established. Here we provide evidence that gut microbiome dysbiosis is associated with translocation of bacteria into the blood during COVID-19, causing life-threatening secondary infections. We first demonstrate SARS-CoV-2 infection induces gut microbiome dysbiosis in mice, which correlated with alterations to Paneth cells and goblet cells, and markers of barrier permeability. Samples collected from 96 COVID-19 patients at two different clinical sites also revealed substantial gut microbiome dysbiosis, including blooms of opportunistic pathogenic bacterial genera known to include antimicrobial-resistant species. Analysis of blood culture results testing for secondary microbial bloodstream infections with paired microbiome data indicates that bacteria may translocate from the gut into the systemic circulation of COVID-19 patients. These results are consistent with a direct role for gut microbiome dysbiosis in enabling dangerous secondary infections during COVID-19.
    DOI:  https://doi.org/10.1038/s41467-022-33395-6
  35. Nat Genet. 2022 Nov 04.
    Multi-ancestry genome-wide association analyses identify novel genetic mechanisms in rheumatoid arthritis.
    BioBank Japan Project
      Rheumatoid arthritis (RA) is a highly heritable complex disease with unknown etiology. Multi-ancestry genetic research of RA promises to improve power to detect genetic signals, fine-mapping resolution and performances of polygenic risk scores (PRS). Here, we present a large-scale genome-wide association study (GWAS) of RA, which includes 276,020 samples from five ancestral groups. We conducted a multi-ancestry meta-analysis and identified 124 loci (P < 5 × 10-8), of which 34 are novel. Candidate genes at the novel loci suggest essential roles of the immune system (for example, TNIP2 and TNFRSF11A) and joint tissues (for example, WISP1) in RA etiology. Multi-ancestry fine-mapping identified putatively causal variants with biological insights (for example, LEF1). Moreover, PRS based on multi-ancestry GWAS outperformed PRS based on single-ancestry GWAS and had comparable performance between populations of European and East Asian ancestries. Our study provides several insights into the etiology of RA and improves the genetic predictability of RA.
    DOI:  https://doi.org/10.1038/s41588-022-01213-w
  36. Nat Commun. 2022 Nov 04. 13(1): 6656
    Metabolite annotation from knowns to unknowns through knowledge-guided multi-layer metabolic networking.
    Zhiwei Zhou, Mingdu Luo, Haosong Zhang, Yandong Yin, Yuping Cai, Zheng-Jiang Zhu.
      Liquid chromatography - mass spectrometry (LC-MS) based untargeted metabolomics allows to measure both known and unknown metabolites in the metabolome. However, unknown metabolite annotation is a major challenge in untargeted metabolomics. Here, we develop an approach, namely, knowledge-guided multi-layer network (KGMN), to enable global metabolite annotation from knowns to unknowns in untargeted metabolomics. The KGMN approach integrates three-layer networks, including knowledge-based metabolic reaction network, knowledge-guided MS/MS similarity network, and global peak correlation network. To demonstrate the principle, we apply KGMN in an in vitro enzymatic reaction system and different biological samples, with ~100-300 putative unknowns annotated in each data set. Among them, >80% unknown metabolites are corroborated with in silico MS/MS tools. Finally, we validate 5 metabolites that are absent in common MS/MS libraries through repository mining and synthesis of chemical standards. Together, the KGMN approach enables efficient unknown annotations, and substantially advances the discovery of recurrent unknown metabolites for common biological samples from model organisms, towards deciphering dark matter in untargeted metabolomics.
    DOI:  https://doi.org/10.1038/s41467-022-34537-6
  37. Nat Commun. 2022 Nov 04. 13(1): 6562
    A genetically encoded fluorescent biosensor for detecting itaconate with subcellular resolution in living macrophages.
    Pengkai Sun, Zhenxing Zhang, Bin Wang, Caiyun Liu, Chao Chen, Ping Liu, Xinjian Li.
      Itaconate is a newly discovered endogenous metabolite promoting an anti-inflammatory program during innate immune response, but the precise mechanisms underlying its effect remains poorly understood owing primarily to the limitations of available itaconate-monitoring techniques. Here, we develop and validate a genetically encoded fluorescent itaconate biosensor, BioITA, for directly monitoring itaconate dynamics in subcellular compartments of living macrophages. Utilizing BioITA, we monitor the itaconate dynamics in response to lipopolysaccharide (LPS) stimulation in the context of modulating itaconate transportation and metabolism. Moreover, we show that STING activation induces itaconate production, and injection of AAVs expressing cytosolic BioITA into mice allows directly reporting elevation of itaconate level in activated macrophages derived from LPS-injected mice. Thus, BioITA enables subcellular resolution imaging of itaconate in living macrophages.
    DOI:  https://doi.org/10.1038/s41467-022-34306-5
  38. Nature. 2022 Nov 04.
    Audio long read: The controversial embryo tests that promise a better baby.
    Max Kozlov, Benjamin Thompson.
      
    Keywords:  Diseases; Policy; SARS-CoV-2
    DOI:  https://doi.org/10.1038/d41586-022-03295-2
  39. Nat Commun. 2022 Nov 02. 13(1): 6578
    Enhancer decommissioning by MLL4 ablation elicits dsRNA-interferon signaling and GSDMD-mediated pyroptosis to potentiate anti-tumor immunity.
    Hanhan Ning, Shan Huang, Yang Lei, Renyong Zhi, Han Yan, Jiaxing Jin, Zhenyu Hu, Kaimin Guo, Jinhua Liu, Jie Yang, Zhe Liu, Yi Ba, Xin Gao, Deqing Hu.
      Enhancer deregulation is a well-established pro-tumorigenic mechanism but whether it plays a regulatory role in tumor immunity is largely unknown. Here, we demonstrate that tumor cell ablation of mixed-lineage leukemia 3 and 4 (MLL3 and MLL4, also known as KMT2C and KMT2D, respectively), two enhancer-associated histone H3 lysine 4 (H3K4) mono-methyltransferases, increases tumor immunogenicity and promotes anti-tumor T cell response. Mechanistically, MLL4 ablation attenuates the expression of RNA-induced silencing complex (RISC) and DNA methyltransferases through decommissioning enhancers/super-enhancers, which consequently lead to transcriptional reactivation of the double-stranded RNA (dsRNA)-interferon response and gasdermin D (GSDMD)-mediated pyroptosis, respectively. More importantly, we reveal that both the dsRNA-interferon signaling and GSDMD-mediated pyroptosis are of critical importance to the increased anti-tumor immunity and improved immunotherapeutic efficacy in MLL4-ablated tumors. Thus, our findings establish tumor cell enhancers as an additional layer of immune evasion mechanisms and suggest the potential of targeting enhancers or their upstream and/or downstream molecular pathways to overcome immunotherapeutic resistance in cancer patients.
    DOI:  https://doi.org/10.1038/s41467-022-34253-1
  40. Nat Commun. 2022 Nov 02. 13(1): 6577
    Phosphorylation of 17β-hydroxysteroid dehydrogenase 13 at serine 33 attenuates nonalcoholic fatty liver disease in mice.
    Wen Su, Sijin Wu, Yongliang Yang, Yanlin Guo, Haibo Zhang, Jie Su, Lei Chen, Zhuo Mao, Rongfeng Lan, Rong Cao, Chunjiong Wang, Hu Xu, Cong Zhang, Sha Li, Min Gao, Xiaocong Chen, Zhiyou Zheng, Bing Wang, Yi'ao Liu, Zuojun Liu, Zimei Wang, Baohua Liu, Xinmin Fan, Xiaoyan Zhang, Youfei Guan.
      17β-hydroxysteroid dehydrogenase-13 is a hepatocyte-specific, lipid droplet-associated protein. A common loss-of-function variant of HSD17B13 (rs72613567: TA) protects patients against non-alcoholic fatty liver disease with underlying mechanism incompletely understood. In the present study, we identify the serine 33 of 17β-HSD13 as an evolutionally conserved PKA target site and its phosphorylation facilitates lipolysis by promoting its interaction with ATGL on lipid droplets. Targeted mutation of Ser33 to Ala (S33A) decreases ATGL-dependent lipolysis in cultured hepatocytes by reducing CGI-58-mediated ATGL activation. Importantly, a transgenic knock-in mouse strain carrying the HSD17B13 S33A mutation (HSD17B1333A/A) spontaneously develops hepatic steatosis with reduced lipolysis and increased inflammation. Moreover, Hsd17B1333A/A mice are more susceptible to high-fat diet-induced nonalcoholic steatohepatitis. Finally, we find reproterol, a potential 17β-HSD13 modulator and FDA-approved drug, confers a protection against nonalcoholic steatohepatitis via PKA-mediated Ser33 phosphorylation of 17β-HSD13. Therefore, targeting the Ser33 phosphorylation site could represent a potential approach to treat NASH.
    DOI:  https://doi.org/10.1038/s41467-022-34299-1
  41. Sci Adv. 2022 Nov 04. 8(44): eabn5631
    Multiplexed high-throughput immune cell imaging reveals molecular health-associated phenotypes.
    Yannik Severin, Benjamin D Hale, Julien Mena, David Goslings, Beat M Frey, Berend Snijder.
      Phenotypic plasticity is essential to the immune system, yet the factors that shape it are not fully understood. Here, we comprehensively analyze immune cell phenotypes including morphology across human cohorts by single-round multiplexed immunofluorescence, automated microscopy, and deep learning. Using the uncertainty of convolutional neural networks to cluster the phenotypes of eight distinct immune cell subsets, we find that the resulting maps are influenced by donor age, gender, and blood pressure, revealing distinct polarization and activation-associated phenotypes across immune cell classes. We further associate T cell morphology to transcriptional state based on their joint donor variability and validate an inflammation-associated polarized T cell morphology and an age-associated loss of mitochondria in CD4+ T cells. Together, we show that immune cell phenotypes reflect both molecular and personal health information, opening new perspectives into the deep immune phenotyping of individual people in health and disease.
    DOI:  https://doi.org/10.1126/sciadv.abn5631
  42. Nat Commun. 2022 Oct 29. 13(1): 6461
    Gi/o protein-coupled receptor inhibition of beta-cell electrical excitability and insulin secretion depends on Na+/K+ ATPase activation.
    Matthew T Dickerson, Prasanna K Dadi, Karolina E Zaborska, Arya Y Nakhe, Charles M Schaub, Jordyn R Dobson, Nicole M Wright, Joshua C Lynch, Claire F Scott, Logan D Robinson, David A Jacobson.
      Gi/o-coupled somatostatin or α2-adrenergic receptor activation stimulated β-cell NKA activity, resulting in islet Ca2+ fluctuations. Furthermore, intra-islet paracrine activation of β-cell Gi/o-GPCRs and NKAs by δ-cell somatostatin secretion slowed Ca2+ oscillations, which decreased insulin secretion. β-cell membrane potential hyperpolarization resulting from Gi/o-GPCR activation was dependent on NKA phosphorylation by Src tyrosine kinases. Whereas, β-cell NKA function was inhibited by cAMP-dependent PKA activity. These data reveal that NKA-mediated β-cell membrane potential hyperpolarization is the primary and conserved mechanism for Gi/o-GPCR control of electrical excitability, Ca2+ handling, and insulin secretion.
    DOI:  https://doi.org/10.1038/s41467-022-34166-z
  43. Circulation. 2022 Nov 02.
    Pathogenesis of Cardiomyopathy Caused by Variants in ALPK3, an Essential Pseudokinase in the Cardiomyocyte Nucleus and Sarcomere.
    Radhika Agarwal, Hiroko Wakimoto, Joao A Paulo, Qi Zhang, Daniel Reichart, Christopher Toepfer, Arun Sharma, Angela C Tai, Mingyue Lun, Joshua Gorham, Steven R DePalma, Steven P Gygi, J G Seidman, Christine E Seidman.
      BACKGROUND: ALPK3 encodes α-kinase 3, a muscle-specific protein of unknown function. ALPK3 loss-of-function variants cause cardiomyopathy with distinctive clinical manifestations in both children and adults, but the molecular functions of ALPK3 remain poorly understood.METHODS: We explored the putative kinase activity of ALPK3 and the consequences of damaging variants using isogenic human induced pluripotent stem cell-derived cardiomyocytes, mice, and human patient tissues.
    RESULTS: Multiple sequence alignment of all human α-kinase domains and their orthologs revealed 4 conserved residues that were variant only in ALPK3, demonstrating evolutionary divergence of the ALPK3 α-kinase domain sequence. Phosphoproteomic evaluation of both ALPK3 kinase domain inhibition and overexpression failed to detect significant changes in catalytic activity, establishing ALPK3 as a pseudokinase. Investigations into alternative functions revealed that ALPK3 colocalized with myomesin proteins (MYOM1, MYOM2) at both the nuclear envelope and the sarcomere M-band. ALPK3 loss-of-function variants caused myomesin proteins to mislocalize and also dysregulated several additional M-band proteins involved in sarcomere protein turnover, which ultimately impaired cardiomyocyte structure and function.
    CONCLUSIONS: ALPK3 is an essential cardiac pseudokinase that inserts in the nuclear envelope and the sarcomere M-band. Loss of ALPK3 causes mislocalization of myomesins, critical force-buffering proteins in cardiomyocytes, and also dysregulates M-band proteins necessary for sarcomere protein turnover. We conclude that ALPK3 cardiomyopathy induces ventricular dilatation caused by insufficient myomesin-mediated force buffering and hypertrophy by impairment of sarcomere proteostasis.
    Keywords:  M-band; cardiomyopathy; hiPSC-CM; phosphoproteomics; pseudokinase, α-kinase; sarcomere
    DOI:  https://doi.org/10.1161/CIRCULATIONAHA.122.059688
  44. Cell. 2022 Oct 25. pii: S0092-8674(22)01255-7. [Epub ahead of print]
    Multiphase coalescence mediates Hippo pathway activation.
    Li Wang, Kyungsuk Choi, Ting Su, Bing Li, Xiaofeng Wu, Ruihui Zhang, Jordan H Driskill, Hongde Li, Huiyan Lei, Pengfei Guo, Elizabeth H Chen, Yonggang Zheng, Duojia Pan.
      The function of biomolecular condensates is often restricted by condensate dissolution. Whether condensates can be suppressed without condensate dissolution is unclear. Here, we show that upstream regulators of the Hippo signaling pathway form functionally antagonizing condensates, and their coalescence into a common phase provides a mode of counteracting the function of biomolecular condensates without condensate dissolution. Specifically, the negative regulator SLMAP forms Hippo-inactivating condensates to facilitate pathway inhibition by the STRIPAK complex. In response to cell-cell contact or osmotic stress, the positive regulators AMOT and KIBRA form Hippo-activating condensates to facilitate pathway activation. The functionally antagonizing SLMAP and AMOT/KIBRA condensates further coalesce into a common phase to inhibit STRIPAK function. These findings provide a paradigm for restricting the activity of biomolecular condensates without condensate dissolution, shed light on the molecular principles of multiphase organization, and offer a conceptual framework for understanding upstream regulation of the Hippo signaling pathway.
    Keywords:  AMOT; Hippo pathway; KIBRA; STRIPAK; YAP; biomolecular condensates; cell-cell contact; cytoskeleton; multiphase; osmotic stress
    DOI:  https://doi.org/10.1016/j.cell.2022.09.036
  45. Nat Commun. 2022 Oct 31. 13(1): 6512
    Plasma membrane flipping of Syntaxin-2 regulates its inhibitory action on insulin granule exocytosis.
    Fei Kang, Li Xie, Tairan Qin, Yifan Miao, Youhou Kang, Toshimasa Takahashi, Tao Liang, Huanli Xie, Herbert Y Gaisano.
      Enhancing pancreatic β-cell secretion is a primary therapeutic target for type-2 diabetes (T2D). Syntaxin-2 (Stx2) has just been identified to be an inhibitory SNARE for insulin granule exocytosis, holding potential as a treatment for T2D, yet its molecular underpinnings remain unclear. We show that excessive Stx2 recruitment to raft-like granule docking sites at higher binding affinity than pro-fusion syntaxin-1A effectively competes for and inhibits fusogenic SNARE machineries. Depletion of Stx2 in human β-cells improves insulin secretion by enhancing trans-SNARE complex assembly and cis-SNARE disassembly. Using a genetically-encoded reporter, glucose stimulation is shown to induce Stx2 flipping across the plasma membrane, which relieves its suppression of cytoplasmic fusogenic SNARE complexes to promote insulin secretion. Targeting the flipping efficiency of Stx2 profoundly modulates secretion, which could restore the impaired insulin secretion in diabetes. Here, we show that Stx2 acts to assist this precise tuning of insulin secretion in β-cells, including in diabetes.
    DOI:  https://doi.org/10.1038/s41467-022-33986-3
  46. Cell Rep. 2022 Nov 01. pii: S2211-1247(22)01440-1. [Epub ahead of print]41(5): 111579
    Melanocortin-4 receptors activate sympathetic preganglionic neurons and elevate blood pressure via TRPV1.
    Sang Hyeon Ju, Hyeonju Yun, Youjin Oh, Yeeun Choi, Jong-Woo Sohn.
      Melanocortin-4 receptors (MC4Rs) expressed by the central nervous system are essential regulators of energy homeostasis, and Mc4r mutation is the most common cause of human monogenic obesity. Notably, patients with obesity carrying Mc4r mutations are protected against obesity-induced hypertension, and MC4R agonists elevate blood pressure (BP). Although increased sympathetic tone by MC4Rs is suggested to underlie this phenotype, the detailed mechanisms remain unclear. Here, we investigate how MC4Rs regulate the sympathetic preganglionic neurons and find that MC4Rs activate these neurons via the protein kinase A-dependent activation of the transient receptor potential vanilloid 1 (TRPV1) channel. Importantly, we demonstrate that the inhibition of TRPV1 prevents MC4R-induced elevation of BP but does not affect MC4R-induced anorexia. We further show that TRPV1 is responsible for MC4R-dependent activation of the sympathetic preganglionic neurons by high-fat diet. Together, our results provide insight into how MC4Rs regulate sympathetic function.
    Keywords:  CP: Metabolism; CP: Neuroscience; appetite; autonomic nervous system; blood pressure; hypertension; obesity
    DOI:  https://doi.org/10.1016/j.celrep.2022.111579
  47. Nature. 2022 Nov 02.
    Blocking PD-L1-PD-1 improves senescence surveillance and ageing phenotypes.
    Teh-Wei Wang, Yoshikazu Johmura, Narumi Suzuki, Satotaka Omori, Toshiro Migita, Kiyoshi Yamaguchi, Seira Hatakeyama, Satoshi Yamazaki, Eigo Shimizu, Seiya Imoto, Yoichi Furukawa, Akihiko Yoshimura, Makoto Nakanishi.
      The accumulation of senescent cells is a major cause of age-related inflammation and predisposes to a variety of age-related diseases1. However, little is known about the molecular basis underlying this accumulation and its potential as a target to ameliorate the ageing process. Here we show that senescent cells heterogeneously express the immune checkpoint protein programmed death-ligand 1 (PD-L1) and that PD-L1+ senescent cells accumulate with age in vivo. PD-L1- cells are sensitive to T cell surveillance, whereas PD-L1+ cells are resistant, even in the presence of senescence-associated secretory phenotypes (SASP). Single-cell analysis of p16+ cells in vivo revealed that PD-L1 expression correlated with higher levels of SASP. Consistent with this, administration of programmed cell death protein 1 (PD-1) antibody to naturally ageing mice or a mouse model with normal livers or induced nonalcoholic steatohepatitis reduces the total number of p16+ cells in vivo as well as the PD-L1+ population in an activated CD8+ T cell-dependent manner, ameliorating various ageing-related phenotypes. These results suggest that the heterogeneous expression of PD-L1 has an important role in the accumulation of senescent cells and inflammation associated with ageing, and the elimination of PD-L1+ senescent cells by immune checkpoint blockade may be a promising strategy for anti-ageing therapy.
    DOI:  https://doi.org/10.1038/s41586-022-05388-4
  48. Nat Commun. 2022 Nov 02. 13(1): 6580
    Tempo: an unsupervised Bayesian algorithm for circadian phase inference in single-cell transcriptomics.
    Benjamin J Auerbach, Garret A FitzGerald, Mingyao Li.
      The circadian clock is a 24 h cellular timekeeping mechanism that regulates human physiology. Answering several fundamental questions in circadian biology will require joint measures of single-cell circadian phases and transcriptomes. However, no widespread experimental approaches exist for this purpose. While computational approaches exist to infer cell phase directly from single-cell RNA-sequencing data, existing methods yield poor circadian phase estimates, and do not quantify estimation uncertainty, which is essential for interpretation of results from very sparse single-cell RNA-sequencing data. To address these unmet needs, we introduce Tempo, a Bayesian variational inference approach that incorporates domain knowledge of the clock and quantifies phase estimation uncertainty. Through simulations and analyses of real data, we demonstrate that Tempo yields more accurate estimates of circadian phase than existing methods and provides well-calibrated uncertainty quantifications. Tempo will facilitate large-scale studies of single-cell circadian transcription.
    DOI:  https://doi.org/10.1038/s41467-022-34185-w
  49. Stem Cell Reports. 2022 Oct 27. pii: S2213-6711(22)00501-X. [Epub ahead of print]
    BRD9-containing non-canonical BAF complex maintains somatic cell transcriptome and acts as a barrier to human reprogramming.
    Kenan Sevinç, Gülben Gürhan Sevinç, Ayşe Derya Cavga, Martin Philpott, Simge Kelekçi, Hazal Can, Adam P Cribbs, Abdullah Burak Yıldız, Alperen Yılmaz, Enes Sefa Ayar, Dilşad H Arabacı, James E Dunford, Deniz Ata, Logan H Sigua, Jun Qi, Udo Oppermann, Tamer T Onder.
      Epigenetic reprogramming to pluripotency requires extensive remodeling of chromatin landscapes to silence existing cell-type-specific genes and activate pluripotency genes. ATP-dependent chromatin remodeling complexes are important regulators of chromatin structure and gene expression; however, the role of recently identified Bromodomain-containing protein 9 (BRD9) and the associated non-canonical BRG1-associated factors (ncBAF) complex in reprogramming remains unknown. Here, we show that genetic or chemical inhibition of BRD9, as well as ncBAF complex subunit GLTSCR1, but not the closely related BRD7, increase human somatic cell reprogramming efficiency and can replace KLF4 and c-MYC. We find that BRD9 is dispensable for human induced pluripotent stem cells under primed but not under naive conditions. Mechanistically, BRD9 inhibition downregulates fibroblast-related genes and decreases chromatin accessibility at somatic enhancers. BRD9 maintains the expression of transcriptional regulators MN1 and ZBTB38, both of which impede reprogramming. Collectively, these results establish BRD9 as an important safeguarding factor for somatic cell identity whose inhibition lowers chromatin-based barriers to reprogramming.
    Keywords:  BRD9; chromatin remodeling; iPSC; naive and primed pluripotency; reprogramming
    DOI:  https://doi.org/10.1016/j.stemcr.2022.10.005
  50. Nature. 2022 Nov 02.
    Neuropeptide regulation of non-redundant ILC2 responses at barrier surfaces.
    JRI IBD Live Cell Bank Consortium
      Emerging studies indicate that cooperation between neurons and immune cells regulates antimicrobial immunity, inflammation and tissue homeostasis. For example, a neuronal rheostat provides excitatory or inhibitory signals that control the functions of tissue-resident group 2 innate lymphoid cells (ILC2s) at mucosal barrier surfaces1-4. ILC2s express NMUR1, a receptor for neuromedin U (NMU), which is a prominent cholinergic neuropeptide that promotes ILC2 responses5-7. However, many functions of ILC2s are shared with adaptive lymphocytes, including the production of type 2 cytokines8,9 and the release of tissue-protective amphiregulin (AREG)10-12. Consequently, there is controversy regarding whether innate lymphoid cells and adaptive lymphocytes perform redundant or non-redundant functions13-15. Here we generate a new genetic tool to target ILC2s for depletion or gene deletion in the presence of an intact adaptive immune system. Transgenic expression of iCre recombinase under the control of the mouse Nmur1 promoter enabled ILC2-specific deletion of AREG. This revealed that ILC2-derived AREG promotes non-redundant functions in the context of antiparasite immunity and tissue protection following intestinal damage and inflammation. Notably, NMU expression levels increased in inflamed intestinal tissues from both mice and humans, and NMU induced AREG production in mouse and human ILC2s. These results indicate that neuropeptide-mediated regulation of non-redundant functions of ILC2s is an evolutionarily conserved mechanism that integrates immunity and tissue protection.
    DOI:  https://doi.org/10.1038/s41586-022-05297-6
  51. Nat Commun. 2022 Oct 30. 13(1): 6491
    Sexually dimorphic estrogen sensing in skeletal stem cells controls skeletal regeneration.
    Tom W Andrew, Lauren S Koepke, Yuting Wang, Michael Lopez, Holly Steininger, Danielle Struck, Tatiana Boyko, Thomas H Ambrosi, Xinming Tong, Yuxi Sun, Gunsagar S Gulati, Matthew P Murphy, Owen Marecic, Ruth Telvin, Katharina Schallmoser, Dirk Strunk, Jun Seita, Stuart B Goodman, Fan Yang, Michael T Longaker, George P Yang, Charles K F Chan.
      Sexually dimorphic tissues are formed by cells that are regulated by sex hormones. While a number of systemic hormones and transcription factors are known to regulate proliferation and differentiation of osteoblasts and osteoclasts, the mechanisms that determine sexually dimorphic differences in bone regeneration are unclear. To explore how sex hormones regulate bone regeneration, we compared bone fracture repair between adult male and female mice. We found that skeletal stem cell (SSC) mediated regeneration in female mice is dependent on estrogen signaling but SSCs from male mice do not exhibit similar estrogen responsiveness. Mechanistically, we found that estrogen acts directly on the SSC lineage in mice and humans by up-regulating multiple skeletogenic pathways and is necessary for the stem cell's ability to self- renew and differentiate. Our results also suggest a clinically applicable strategy to accelerate bone healing using localized estrogen hormone therapy.
    DOI:  https://doi.org/10.1038/s41467-022-34063-5
  52. Nature. 2022 Nov 02.
    Inulin fibre promotes microbiota-derived bile acids and type 2 inflammation.
    JRI IBD Live Cell Bank Consortium
      Dietary fibres can exert beneficial anti-inflammatory effects through microbially fermented short-chain fatty acid metabolites1,2, although the immunoregulatory roles of most fibre diets and their microbiota-derived metabolites remain poorly defined. Here, using microbial sequencing and untargeted metabolomics, we show that a diet of inulin fibre alters the composition of the mouse microbiota and the levels of microbiota-derived metabolites, notably bile acids. This metabolomic shift is associated with type 2 inflammation in the intestine and lungs, characterized by IL-33 production, activation of group 2 innate lymphoid cells and eosinophilia. Delivery of cholic acid mimics inulin-induced type 2 inflammation, whereas deletion of the bile acid receptor farnesoid X receptor diminishes the effects of inulin. The effects of inulin are microbiota dependent and were reproduced in mice colonized with human-derived microbiota. Furthermore, genetic deletion of a bile-acid-metabolizing enzyme in one bacterial species abolishes the ability of inulin to trigger type 2 inflammation. Finally, we demonstrate that inulin enhances allergen- and helminth-induced type 2 inflammation. Taken together, these data reveal that dietary inulin fibre triggers microbiota-derived cholic acid and type 2 inflammation at barrier surfaces with implications for understanding the pathophysiology of allergic inflammation, tissue protection and host defence.
    DOI:  https://doi.org/10.1038/s41586-022-05380-y
  53. Nat Commun. 2022 Nov 04. 13(1): 6663
    Lamin A/C-dependent chromatin architecture safeguards naïve pluripotency to prevent aberrant cardiovascular cell fate and function.
    Yinuo Wang, Adel Elsherbiny, Linda Kessler, Julio Cordero, Haojie Shi, Heike Serke, Olga Lityagina, Felix A Trogisch, Mona Malek Mohammadi, Ibrahim El-Battrawy, Johannes Backs, Thomas Wieland, Joerg Heineke, Gergana Dobreva.
      Tight control of cell fate choices is crucial for normal development. Here we show that lamin A/C plays a key role in chromatin organization in embryonic stem cells (ESCs), which safeguards naïve pluripotency and ensures proper cell fate choices during cardiogenesis. We report changes in chromatin compaction and localization of cardiac genes in Lmna-/- ESCs resulting in precocious activation of a transcriptional program promoting cardiomyocyte versus endothelial cell fate. This is accompanied by premature cardiomyocyte differentiation, cell cycle withdrawal and abnormal contractility. Gata4 is activated by lamin A/C loss and Gata4 silencing or haploinsufficiency rescues the aberrant cardiovascular cell fate choices induced by lamin A/C deficiency. We uncover divergent functions of lamin A/C in naïve pluripotent stem cells and cardiomyocytes, which have distinct contributions to the transcriptional alterations of patients with LMNA-associated cardiomyopathy. We conclude that disruption of lamin A/C-dependent chromatin architecture in ESCs is a primary event in LMNA loss-of-function cardiomyopathy.
    DOI:  https://doi.org/10.1038/s41467-022-34366-7
  54. Nature. 2022 Nov 02.
    Nociceptor neurons affect cancer immunosurveillance.
    Mohammad Balood, Maryam Ahmadi, Tuany Eichwald, Ali Ahmadi, Abdelilah Majdoubi, Karine Roversi, Katiane Roversi, Christopher T Lucido, Anthony C Restaino, Siyi Huang, Lexiang Ji, Kai-Chih Huang, Elise Semerena, Sini C Thomas, Alexandro E Trevino, Hannah Merrison, Alexandre Parrin, Benjamin Doyle, Daniel W Vermeer, William C Spanos, Caitlin S Williamson, Corey R Seehus, Simmie L Foster, Hongyue Dai, Chengyi J Shu, Manu Rangachari, Jacques Thibodeau, Sonia V Del Rincon, Ronny Drapkin, Moutih Rafei, Nader Ghasemlou, Paola D Vermeer, Clifford J Woolf, Sebastien Talbot.
      Solid tumours are innervated by nerve fibres that arise from the autonomic and sensory peripheral nervous systems1-5. Whether the neo-innervation of tumours by pain-initiating sensory neurons affects cancer immunosurveillance remains unclear. Here we show that melanoma cells interact with nociceptor neurons, leading to increases in their neurite outgrowth, responsiveness to noxious ligands and neuropeptide release. Calcitonin gene-related peptide (CGRP)-one such nociceptor-produced neuropeptide-directly increases the exhaustion of cytotoxic CD8+ T cells, which limits their capacity to eliminate melanoma. Genetic ablation of the TRPV1 lineage, local pharmacological silencing of nociceptors and antagonism of the CGRP receptor RAMP1 all reduced the exhaustion of tumour-infiltrating leukocytes and decreased the growth of tumours, nearly tripling the survival rate of mice that were inoculated with B16F10 melanoma cells. Conversely, CD8+ T cell exhaustion was rescued in sensory-neuron-depleted mice that were treated with local recombinant CGRP. As compared with wild-type CD8+ T cells, Ramp1-/- CD8+ T cells were protected against exhaustion when co-transplanted into tumour-bearing Rag1-deficient mice. Single-cell RNA sequencing of biopsies from patients with melanoma revealed that intratumoral RAMP1-expressing CD8+ T cells were more exhausted than their RAMP1-negative counterparts, whereas overexpression of RAMP1 correlated with a poorer clinical prognosis. Overall, our results suggest that reducing the release of CGRP from tumour-innervating nociceptors could be a strategy to improve anti-tumour immunity by eliminating the immunomodulatory effects of CGRP on cytotoxic CD8+ T cells.
    DOI:  https://doi.org/10.1038/s41586-022-05374-w
  55. Nat Commun. 2022 Nov 02. 13(1): 6579
    MYC promotes immune-suppression in triple-negative breast cancer via inhibition of interferon signaling.
    Dario Zimmerli, Chiara S Brambillasca, Francien Talens, Jinhyuk Bhin, Renske Linstra, Lou Romanens, Arkajyoti Bhattacharya, Stacey E P Joosten, Ana Moises Da Silva, Nuno Padrao, Max D Wellenstein, Kelly Kersten, Mart de Boo, Maurits Roorda, Linda Henneman, Roebi de Bruijn, Stefano Annunziato, Eline van der Burg, Anne Paulien Drenth, Catrin Lutz, Theresa Endres, Marieke van de Ven, Martin Eilers, Lodewyk Wessels, Karin E de Visser, Wilbert Zwart, Rudolf S N Fehrmann, Marcel A T M van Vugt, Jos Jonkers.
      The limited efficacy of immune checkpoint inhibitor treatment in triple-negative breast cancer (TNBC) patients is attributed to sparse or unresponsive tumor-infiltrating lymphocytes, but the mechanisms that lead to a therapy resistant tumor immune microenvironment are incompletely known. Here we show a strong correlation between MYC expression and loss of immune signatures in human TNBC. In mouse models of TNBC proficient or deficient of breast cancer type 1 susceptibility gene (BRCA1), MYC overexpression dramatically decreases lymphocyte infiltration in tumors, along with immune signature remodelling. MYC-mediated suppression of inflammatory signalling induced by BRCA1/2 inactivation is confirmed in human TNBC cell lines. Moreover, MYC overexpression prevents the recruitment and activation of lymphocytes in both human and mouse TNBC co-culture models. Chromatin-immunoprecipitation-sequencing reveals that MYC, together with its co-repressor MIZ1, directly binds promoters of multiple interferon-signalling genes, resulting in their downregulation. MYC overexpression thus counters tumor growth inhibition by a Stimulator of Interferon Genes (STING) agonist via suppressing induction of interferon signalling. Together, our data reveal that MYC suppresses innate immunity and facilitates tumor immune escape, explaining the poor immunogenicity of MYC-overexpressing TNBCs.
    DOI:  https://doi.org/10.1038/s41467-022-34000-6
  56. Nat Commun. 2022 Oct 29. 13(1): 6458
    Single-cell profiling reveals distinct adaptive immune hallmarks in MDA5+ dermatomyositis with therapeutic implications.
    Yan Ye, Zechuan Chen, Shan Jiang, Fengyun Jia, Teng Li, Xia Lu, Jing Xue, Xinyue Lian, Jiaqiang Ma, Pei Hao, Liangjing Lu, Shuang Ye, Nan Shen, Chunde Bao, Qiong Fu, Xiaoming Zhang.
      Anti-melanoma differentiation-associated gene 5-positive dermatomyositis (MDA5+ DM) is an autoimmune condition associated with rapidly progressive interstitial lung disease and high mortality. The aetiology and pathogenesis of MDA5+ DM are still largely unknown. Here we describe the immune signatures of MDA5+ DM via single-cell RNA sequencing, flow cytometry and multiplex immunohistochemistry in peripheral B and T cells and in affected lung tissue samples from one patient. We find strong peripheral antibody-secreting cell and CD8+ T cell responses as cellular immune hallmarks, and over-stimulated type I interferon signaling and associated metabolic reprogramming as molecular immune signature in MDA5+ DM. High frequency of circulating ISG15+ CD8+ T cells at baseline predicts poor one-year survival in MDA5+ DM patients. In affected lungs, we find profuse immune cells infiltration, which likely contributes to the pro-fibrotic response via type I interferon production. The importance of type I interferons in MDA5+ DM pathology is further emphasized by our observation in a retrospective cohort of MDA5+ DM patients that combined calcineurin and Janus kinase inhibitor therapy show superior efficacy to calcineurin inhibitor monotherapy. In summary, this study reveals key immune-pathogenic features of MDA5+ DM and provides a potential basis for future tailored therapies.
    DOI:  https://doi.org/10.1038/s41467-022-34145-4
  57. Nat Commun. 2022 Nov 02. 13(1): 6571
    Erratic and blood vessel-guided migration of astrocyte progenitors in the cerebral cortex.
    Hidenori Tabata, Megumi Sasaki, Masakazu Agetsuma, Hitomi Sano, Yuki Hirota, Michio Miyajima, Kanehiro Hayashi, Takao Honda, Masashi Nishikawa, Yutaka Inaguma, Hidenori Ito, Hirohide Takebayashi, Masatsugu Ema, Kazuhiro Ikenaka, Junichi Nabekura, Koh-Ichi Nagata, Kazunori Nakajima.
      Astrocytes are one of the most abundant cell types in the mammalian brain. They play essential roles in synapse formation, maturation, and elimination. However, how astrocytes migrate into the gray matter to accomplish these processes is poorly understood. Here, we show that, by combinational analyses of in vitro and in vivo time-lapse observations and lineage traces, astrocyte progenitors move rapidly and irregularly within the developing cortex, which we call erratic migration. Astrocyte progenitors also adopt blood vessel-guided migration. These highly motile progenitors are generated in the restricted prenatal stages and differentiate into protoplasmic astrocytes in the gray matter, whereas postnatally generated progenitors do not move extensively and differentiate into fibrous astrocytes in the white matter. We found Cxcr4/7, and integrin β1 regulate the blood vessel-guided migration, and their functional blocking disrupts their positioning. This study provides insight into astrocyte development and may contribute to understanding the pathogenesis caused by their defects.
    DOI:  https://doi.org/10.1038/s41467-022-34184-x
  58. Nat Genet. 2022 Nov 04.
    Disrupted β-cell-specific gene silencing causes congenital hyperinsulinism.
      
    DOI:  https://doi.org/10.1038/s41588-022-01206-9
  59. Nat Metab. 2022 Nov 03.
    Adipose tissue macrophages exert systemic metabolic control by manipulating local iron concentrations.
    Nolwenn Joffin, Christy M Gliniak, Jan-Bernd Funcke, Vivian A Paschoal, Clair Crewe, Shiuhwei Chen, Ruth Gordillo, Christine M Kusminski, Da Young Oh, Werner J Geldenhuys, Philipp E Scherer.
      Iron is essential to many fundamental biological processes, but its cellular compartmentalization and concentration must be tightly controlled. Although iron overload can contribute to obesity-associated metabolic deterioration, the subcellular localization and accumulation of iron in adipose tissue macrophages is largely unknown. Here, we show that macrophage mitochondrial iron levels control systemic metabolism in male mice by altering adipocyte iron concentrations. Using various transgenic mouse models to manipulate the macrophage mitochondrial matrix iron content in an inducible fashion, we demonstrate that lowering macrophage mitochondrial matrix iron increases numbers of M2-like macrophages in adipose tissue, lowers iron levels in adipocytes, attenuates inflammation and protects from high-fat-diet-induced metabolic deterioration. Conversely, elevating macrophage mitochondrial matrix iron increases M1-like macrophages and iron levels in adipocytes, exacerbates inflammation and worsens high-fat-diet-induced metabolic dysfunction. These phenotypes are robustly reproduced by transplantation of a small amount of fat from transgenic to wild-type mice. Taken together, we identify macrophage mitochondrial iron levels as a crucial determinant of systemic metabolic homeostasis in mice.
    DOI:  https://doi.org/10.1038/s42255-022-00664-z
  60. Nat Biotechnol. 2022 Oct 31.
    A split, conditionally active mimetic of IL-2 reduces the toxicity of systemic cytokine therapy.
    Alfredo Quijano-Rubio, Aladdin M Bhuiyan, Huilin Yang, Isabel Leung, Elisa Bello, Lestat R Ali, Kevin Zhangxu, Jilliane Perkins, Jung-Ho Chun, Wentao Wang, Marc J Lajoie, Rashmi Ravichandran, Yun-Huai Kuo, Stephanie K Dougan, Stanley R Riddell, Jamie B Spangler, Michael Dougan, Daniel-Adriano Silva, David Baker.
      The therapeutic potential of recombinant cytokines has been limited by the severe side effects of systemic administration. We describe a strategy to reduce the dose-limiting toxicities of monomeric cytokines by designing two components that require colocalization for activity and that can be independently targeted to restrict activity to cells expressing two surface markers. We demonstrate the approach with a previously designed mimetic of cytokines interleukin-2 and interleukin-15-Neoleukin-2/15 (Neo-2/15)-both for trans-activating immune cells surrounding targeted tumor cells and for cis-activating directly targeted immune cells. In trans-activation mode, tumor antigen targeting of the two components enhanced antitumor activity and attenuated toxicity compared with systemic treatment in syngeneic mouse melanoma models. In cis-activation mode, immune cell targeting of the two components selectively expanded CD8+ T cells in a syngeneic mouse melanoma model and promoted chimeric antigen receptor T cell activation in a lymphoma xenograft model, enhancing antitumor efficacy in both cases.
    DOI:  https://doi.org/10.1038/s41587-022-01510-z
  61. Mol Cell. 2022 Oct 31. pii: S1097-2765(22)00962-5. [Epub ahead of print]
    Reversal of mitochondrial malate dehydrogenase 2 enables anaplerosis via redox rescue in respiration-deficient cells.
    Patricia Altea-Manzano, Anke Vandekeere, Joy Edwards-Hicks, Mar Roldan, Emily Abraham, Xhordi Lleshi, Ania Naila Guerrieri, Domenica Berardi, Jimi Wills, Jair Marques Junior, Asimina Pantazi, Juan Carlos Acosta, Rosario M Sanchez-Martin, Sarah-Maria Fendt, Miguel Martin-Hernandez, Andrew J Finch.
      Inhibition of the electron transport chain (ETC) prevents the regeneration of mitochondrial NAD+, resulting in cessation of the oxidative tricarboxylic acid (TCA) cycle and a consequent dependence upon reductive carboxylation for aspartate synthesis. NAD+ regeneration alone in the cytosol can rescue the viability of ETC-deficient cells. Yet, how this occurs and whether transfer of oxidative equivalents to the mitochondrion is required remain unknown. Here, we show that inhibition of the ETC drives reversal of the mitochondrial aspartate transaminase (GOT2) as well as malate and succinate dehydrogenases (MDH2 and SDH) to transfer oxidative NAD+ equivalents into the mitochondrion. This supports the NAD+-dependent activity of the mitochondrial glutamate dehydrogenase (GDH) and thereby enables anaplerosis-the entry of glutamine-derived carbon into the TCA cycle and connected biosynthetic pathways. Thus, under impaired ETC function, the cytosolic redox state is communicated into the mitochondrion and acts as a rheostat to support GDH activity and cell viability.
    Keywords:  anaplerosis; cancer; cancer metabolism; metabolism; mitochondrion; redox; redox transfer; respiration
    DOI:  https://doi.org/10.1016/j.molcel.2022.10.005
  62. J Cell Biol. 2023 Jan 02. pii: e202205045. [Epub ahead of print]222(1):
    V-ATPase/TORC1-mediated ATFS-1 translation directs mitochondrial UPR activation in C. elegans.
    Terytty Yang Li, Arwen W Gao, Xiaoxu Li, Hao Li, Yasmine J Liu, Amelia Lalou, Nagammal Neelagandan, Felix Naef, Kristina Schoonjans, Johan Auwerx.
      To adapt mitochondrial function to the ever-changing intra- and extracellular environment, multiple mitochondrial stress response (MSR) pathways, including the mitochondrial unfolded protein response (UPRmt), have evolved. However, how the mitochondrial stress signal is sensed and relayed to UPRmt transcription factors, such as ATFS-1 in Caenorhabditis elegans, remains largely unknown. Here, we show that a panel of vacuolar H+-ATPase (v-ATPase) subunits and the target of rapamycin complex 1 (TORC1) activity are essential for the cytosolic relay of mitochondrial stress to ATFS-1 and for the induction of the UPRmt. Mechanistically, mitochondrial stress stimulates v-ATPase/Rheb-dependent TORC1 activation, subsequently promoting ATFS-1 translation. Increased translation of ATFS-1 upon mitochondrial stress furthermore relies on a set of ribosomal components but is independent of GCN-2/PEK-1 signaling. Finally, the v-ATPase and ribosomal subunits are required for mitochondrial surveillance and mitochondrial stress-induced longevity. These results reveal a v-ATPase-TORC1-ATFS-1 signaling pathway that links mitochondrial stress to the UPRmt through intimate crosstalks between multiple organelles.
    DOI:  https://doi.org/10.1083/jcb.202205045
  63. Nat Commun. 2022 Nov 04. 13(1): 6647
    2'-5' oligoadenylate synthetase‑like 1 (OASL1) protects against atherosclerosis by maintaining endothelial nitric oxide synthase mRNA stability.
    Tae Kyeong Kim, Sejin Jeon, Seonjun Park, Seong-Keun Sonn, Seungwoon Seo, Joowon Suh, Jing Jin, Hyae Yon Kweon, Sinai Kim, Shin Hye Moon, Okhee Kweon, Bon-Hyeock Koo, Nayoung Kim, Hae-Ock Lee, Young-Myeong Kim, Young-Joon Kim, Sung Ho Park, Goo Taeg Oh.
      Endothelial nitric oxide synthase (eNOS) decreases following inflammatory stimulation. As a master regulator of endothelial homeostasis, maintaining optimal eNOS levels is important during cardiovascular events. However, little is known regarding the mechanism of eNOS protection. In this study, we demonstrate a regulatory role for endothelial expression of 2'-5' oligoadenylate synthetase-like 1 (OASL1) in maintaining eNOS mRNA stability during athero-prone conditions and consider its clinical implications. A lack of endothelial Oasl1 accelerated plaque progression, which was preceded by endothelial dysfunction, elevated vascular inflammation, and decreased NO bioavailability following impaired eNOS expression. Mechanistically, knockdown of PI3K/Akt signaling-dependent OASL expression increased Erk1/2 and NF-κB activation and decreased NOS3 (gene name for eNOS) mRNA expression through upregulation of the negative regulatory, miR-584, whereas a miR-584 inhibitor rescued the effects of OASL knockdown. These results suggest that OASL1/OASL regulates endothelial biology by protecting NOS3 mRNA and targeting miR-584 represents a rational therapeutic strategy for eNOS maintenance in vascular disease.
    DOI:  https://doi.org/10.1038/s41467-022-34433-z
  64. Cell Rep. 2022 Nov 01. pii: S2211-1247(22)01437-1. [Epub ahead of print]41(5): 111576
    Acute depletion of human core nucleoporin reveals direct roles in transcription control but dispensability for 3D genome organization.
    Xiaoyu Zhu, Chuangye Qi, Ruoyu Wang, Joo-Hyung Lee, Jiaofang Shao, Lanxin Bei, Feng Xiong, Phuoc T Nguyen, Guojie Li, Joanna Krakowiak, Su-Pin Koh, Lukas M Simon, Leng Han, Travis I Moore, Wenbo Li.
      The nuclear pore complex (NPC) comprises more than 30 nucleoporins (NUPs) and is a hallmark of eukaryotes. NUPs have been suggested to be important in regulating gene transcription and 3D genome organization. However, evidence in support of their direct roles remains limited. Here, by Cut&Run, we find that core NUPs display broad but also cell-type-specific association with active promoters and enhancers in human cells. Auxin-mediated rapid depletion of two NUPs demonstrates that NUP93, but not NUP35, directly and specifically controls gene transcription. NUP93 directly activates genes with high levels of RNA polymerase II loading and transcriptional elongation by facilitating full BRD4 recruitment to their active enhancers. dCas9-based tethering confirms a direct and causal role of NUP93 in gene transcriptional activation. Unexpectedly, in situ Hi-C and H3K27ac or H3K4me1 HiChIP results upon acute NUP93 depletion show negligible changesS2211-1247(22)01437-1 of 3D genome organization ranging from A/B compartments and topologically associating domains (TADs) to enhancer-promoter contacts.
    Keywords:  3D genome organization; CP: Molecular biology; Cut&Run, PRO-seq; Hi-C; HiChIP; dCas9 tethering; enhancers; nuclear pore complex; nucleoporins; transcription
    DOI:  https://doi.org/10.1016/j.celrep.2022.111576
  65. Diabetes. 2022 Nov 01. pii: db211072. [Epub ahead of print]
    Prostaglandin PGE2 Receptor EP4 Regulates Microglial Phagocytosis and Increases Susceptibility to Diet-Induced Obesity.
    Anzela Niraula, Rachael D Fasnacht, Kelly M Ness, Jeremy M Frey, Sophia A Cuschieri, Mauricio D Dorfman, Joshua P Thaler.
      In rodents, susceptibility to diet-induced obesity requires microglial activation, but the molecular components of this pathway remain incompletely defined. Prostaglandin E2 (PGE2) levels increase in the mediobasal hypothalamus during high fat diet (HFD) feeding, and the PGE2 receptor EP4 regulates microglial activation state and phagocytic activity, suggesting a potential role for microglial EP4 signaling in obesity pathogenesis. To test the role of microglial EP4 in energy balance regulation, we analyzed the metabolic phenotype in a cell-specific EP4 knockout mouse model. Microglial EP4 deletion markedly reduced weight gain and food intake in response to HFD feeding. In correspondence with this lean phenotype, insulin sensitivity was also improved in the HFD-fed MG-EP4 KO mice though glucose tolerance remained surprisingly unaffected. Mechanistically, EP4-deficient microglia showed an attenuated phagocytic state marked by reduced CD68 expression and fewer contacts with POMC neuron processes. These cellular changes observed in the microglial EP4 knockout mice corresponded with an increased density of POMC neurites extending into the paraventricular nucleus. These findings reveal that microglial EP4 signaling promotes body weight gain and insulin resistance during HFD feeding. Furthermore, the data suggest that curbing microglial phagocytic function may preserve POMC cytoarchitecture and PVN input to limit overconsumption during diet-induced obesity.
    DOI:  https://doi.org/10.2337/db21-1072
  66. Nat Immunol. 2022 Oct 31.
    CMTM4 is required for IL-17A signaling.
      
    DOI:  https://doi.org/10.1038/s41590-022-01344-6
  67. J Clin Invest. 2022 Nov 01. pii: e164136. [Epub ahead of print]132(21):
    Inflammation fuels bone marrow exhaustion caused by Samd9l mutation.
    Moonjung Jung.
      Sterile α motif domain-containing 9 (SAMD9) and SAMD9-like (SAMD9L) syndromes are inherited bone marrow failure syndromes known for their frequent development of myelodysplastic syndrome with monosomy 7. In this issue of the JCI, Abdelhamed, Thomas, et al. report a mouse model with a hematopoietic cell-specific heterozygous Samd9l mutation knockin. This mouse model resembles human disease in many ways, including bone marrow failure and the nonrandom loss of the mutant allele. Samd9l-mutant hematopoietic stem progenitor cells showed reduced fitness at baseline, which was further exacerbated by inflammation. TGF-β hyperactivation was found to underlie reduced fitness, which was partially rescued by a TGF-β inhibitor. These findings illustrate the potential role of TGF-β inhibitors in the treatment of SAMD9/SAMD9L syndromes.
    DOI:  https://doi.org/10.1172/JCI164136
  68. Nat Commun. 2022 Nov 01. 13(1): 6527
    Use of a glycomics array to establish the anti-carbohydrate antibody repertoire in type 1 diabetes.
    Paul M H Tran, Fran Dong, Eileen Kim, Katherine P Richardson, Lynn K H Tran, Kathleen Waugh, Diane Hopkins, Richard D Cummings, Peng George Wang, Marian J Rewers, Jin-Xiong She, Sharad Purohit.
      Type 1 diabetes (T1D) is an autoimmune disease, characterized by the presence of autoantibodies to protein and non-protein antigens. Here we report the identification of specific anti-carbohydrate antibodies (ACAs) that are associated with pathogenesis and progression to T1D. We compare circulatory levels of ACAs against 202 glycans in a cross-sectional cohort of T1D patients (n = 278) and healthy controls (n = 298), as well as in a longitudinal cohort (n = 112). We identify 11 clusters of ACAs associated with glycan function class. Clusters enriched for aminoglycosides, blood group A and B antigens, glycolipids, ganglio-series, and O-linked glycans are associated with progression to T1D. ACAs against gentamicin and its related structures, G418 and sisomicin, are also associated with islet autoimmunity. ACAs improve discrimination of T1D status of individuals over a model with only clinical variables and are potential biomarkers for T1D.
    DOI:  https://doi.org/10.1038/s41467-022-34341-2
  69. Sci Immunol. 2022 Nov 11. 7(77): eabm7200
    Oxidized thioredoxin-1 restrains the NLRP1 inflammasome.
    Daniel P Ball, Lydia P Tsamouri, Alvin E Wang, Hsin-Che Huang, Charles D Warren, Qinghui Wang, Isabelle H Edmondson, Andrew R Griswold, Sahana D Rao, Darren C Johnson, Daniel A Bachovchin.
      The danger signals that activate the NLRP1 inflammasome have not been established. Here, we report that the oxidized, but not the reduced, form of thioredoxin-1 (TRX1) binds to NLRP1. We found that oxidized TRX1 associates with the NACHT-LRR region of NLRP1 in an ATP-dependent process, forming a stable complex that restrains inflammasome activation. Consistent with these findings, patient-derived and ATPase-inactivating mutations in the NACHT-LRR region that cause hyperactive inflammasome formation interfere with TRX1 binding. Overall, this work strongly suggests that reductive stress, the cellular perturbation that will eliminate oxidized TRX1 and abrogate the TRX1-NLRP1 interaction, is a danger signal that activates the NLRP1 inflammasome.
    DOI:  https://doi.org/10.1126/sciimmunol.abm7200
  70. Nat Commun. 2022 Oct 29. 13(1): 6459
    Differential trafficking of ligands trogocytosed via CD28 versus CTLA4 promotes collective cellular control of co-stimulation.
    Simon Zenke, Mauricio P Sica, Florian Steinberg, Julia Braun, Alicia Zink, Alina Gavrilov, Alexander Hilger, Aditya Arra, Monika Brunner-Weinzierl, Roland Elling, Niklas Beyersdorf, Tim Lämmermann, Cristian R Smulski, Jan C Rohr.
      Intercellular communication is crucial for collective regulation of cellular behaviors. While clustering T cells have been shown to mutually control the production of key communication signals, it is unclear whether they also jointly regulate their availability and degradation. Here we use newly developed reporter systems, bioinformatic analyses, protein structure modeling and genetic perturbations to assess this. We find that T cells utilize trogocytosis by competing antagonistic receptors to differentially control the abundance of immunoregulatory ligands. Specifically, ligands trogocytosed via CD28 are shuttled to the T cell surface, enabling them to co-stimulate neighboring T cells. In contrast, CTLA4-mediated trogocytosis targets ligands for degradation. Mechanistically, this fate separation is controlled by different acid-sensitivities of receptor-ligand interactions and by the receptor intracellular domains. The ability of CD28 and CTLA4 to confer different fates to trogocytosed ligands reveals an additional layer of collective regulation of cellular behaviors and promotes the robustness of population dynamics.
    DOI:  https://doi.org/10.1038/s41467-022-34156-1
  71. Sci Adv. 2022 Nov 04. 8(44): eabq1263
    Tissue-wide genetic and cellular landscape shapes the execution of sequential PRC2 functions in neural stem cell lineage progression.
    Nicole Amberg, Florian M Pauler, Carmen Streicher, Simon Hippenmeyer.
      The generation of a correctly sized cerebral cortex with all-embracing neuronal and glial cell-type diversity critically depends on faithful radial glial progenitor (RGP) cell proliferation/differentiation programs. Temporal RGP lineage progression is regulated by Polycomb repressive complex 2 (PRC2), and loss of PRC2 activity results in severe neurogenesis defects and microcephaly. How PRC2-dependent gene expression instructs RGP lineage progression is unknown. Here, we use mosaic analysis with double markers (MADM)-based single-cell technology and demonstrate that PRC2 is not cell-autonomously required in neurogenic RGPs but rather acts at the global tissue-wide level. Conversely, cortical astrocyte production and maturation is cell-autonomously controlled by PRC2-dependent transcriptional regulation. We thus reveal highly distinct and sequential PRC2 functions in RGP lineage progression that are dependent on complex interplays between intrinsic and tissue-wide properties. In a broader context, our results imply a critical role for the genetic and cellular niche environment in neural stem cell behavior.
    DOI:  https://doi.org/10.1126/sciadv.abq1263
  72. J Exp Med. 2023 Jan 02. pii: e20220679. [Epub ahead of print]220(1):
    Clonal lineage tracing reveals mechanisms skewing CD8+ T cell fate decisions in chronic infection.
    Moujtaba Y Kasmani, Ryan Zander, H Kay Chung, Yao Chen, Achia Khatun, Martina Damo, Paytsar Topchyan, Kaitlin E Johnson, Darya Levashova, Robert Burns, Ulrike M Lorenz, Vera L Tarakanova, Nikhil S Joshi, Susan M Kaech, Weiguo Cui.
      Although recent evidence demonstrates heterogeneity among CD8+ T cells during chronic infection, developmental relationships and mechanisms underlying their fate decisions remain incompletely understood. Using single-cell RNA and TCR sequencing, we traced the clonal expansion and differentiation of CD8+ T cells during chronic LCMV infection. We identified immense clonal and phenotypic diversity, including a subset termed intermediate cells. Trajectory analyses and infection models showed intermediate cells arise from progenitor cells before bifurcating into terminal effector and exhausted subsets. Genetic ablation experiments identified that type I IFN drives exhaustion through an IRF7-dependent mechanism, possibly through an IFN-stimulated subset bridging progenitor and exhausted cells. Conversely, Zeb2 was critical for generating effector cells. Intriguingly, some T cell clones exhibited lineage bias. Mechanistically, we identified that TCR avidity correlates with an exhausted fate, whereas SHP-1 selectively restricts low-avidity effector cell accumulation. Thus, our work elucidates novel mechanisms underlying CD8+ T cell fate determination during persistent infection and suggests two potential pathways leading to exhaustion.
    DOI:  https://doi.org/10.1084/jem.20220679
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