bims-nimamd Biomed News
on Neuroimmunity and neuroinflammation in ageing and metabolic disease
Issue of 2022‒12‒18
sixty-one papers selected by
Fawaz Alzaïd
Sorbonne Université
  1. A genetic disorder reveals a hematopoietic stem cell regulatory network co-opted in leukemia.
  2. Mitochondrial dysfunction induces ALK5-SMAD2-mediated hypovascularization and arteriovenous malformations in mouse retinas.
  3. A brown fat-enriched adipokine Adissp controls adipose thermogenesis and glucose homeostasis.
  4. Protein import into peroxisomes occurs through a nuclear pore-like phase.
  5. A humanized mouse model to study NK cell biology during HIV infection.
  6. Myeloid cells promote interferon signaling-associated deterioration of the hematopoietic system.
  7. A glutamate receptor C-tail recruits CaMKII to suppress retrograde homeostatic signaling.
  8. Locally organised and activated Fth1hi neutrophils aggravate inflammation of acute lung injury in an IL-10-dependent manner.
  9. Spatial-ID: a cell typing method for spatially resolved transcriptomics via transfer learning and spatial embedding.
  10. Human genetic diversity alters off-target outcomes of therapeutic gene editing.
  11. Prolonged hypernutrition impairs TREM2-dependent efferocytosis to license chronic liver inflammation and NASH development.
  12. Cerebrospinal fluid immune dysregulation during healthy brain aging and cognitive impairment.
  13. Muscle 4EBP1 activation modifies the structure and function of the neuromuscular junction in mice.
  14. Upper gut heat shock proteins HSP70 and GRP78 promote insulin resistance, hyperglycemia, and non-alcoholic steatohepatitis.
  15. Macrophage inflammatory and regenerative response periodicity is programmed by cell cycle and chromatin state.
  16. Targeting cardiomyocyte ADAM10 ectodomain shedding promotes survival early after myocardial infarction.
  17. Neutrophil trafficking to the site of infection requires Cpt1a-dependent fatty acid β-oxidation.
  18. LepRb cell-specific deletion of Slug mitigates obesity and NAFLD.
  19. Aging-associated HELIOS deficiency in naive CD4+ T cells alters chromatin remodeling and promotes effector cell responses.
  20. IRF2 integrates inflammatory signals to balance T cell exhaustion.
  21. Sirt6 attenuates chondrocyte senescence and osteoarthritis progression.
  22. Finger-palm synergistic soft gripper for dynamic capture via energy harvesting and dissipation.
  23. Widespread transposon co-option in the Caenorhabditis germline regulatory network.
  24. Human CARMIL2 deficiency underlies a broader immunological and clinical phenotype than CD28 deficiency.
  25. SIRT7 suppresses energy expenditure and thermogenesis by regulating brown adipose tissue functions in mice.
  26. Engineered cell entry links receptor biology with single-cell genomics.
  27. cDC1-derived IL-27 regulates small intestinal CD4+ T cell homeostasis in mice.
  28. Multidimensional control of therapeutic human cell function with synthetic gene circuits.
  29. PRDM1/BLIMP1 induces cancer immune evasion by modulating the USP22-SPI1-PD-L1 axis in hepatocellular carcinoma cells.
  30. Deep brain stimulation creates informational lesion through membrane depolarization in mouse hippocampus.
  31. Activation of a transient progenitor state in the epicardium is required for zebrafish heart regeneration.
  32. The mitochondrial UPR regulator ATF5 promotes intestinal barrier function via control of the satiety response.
  33. Repurposing a tricyclic antidepressant in tumor and metabolism disease treatment through fatty acid uptake inhibition.
  34. TATTOO-seq delineates spatial and cell type-specific regulatory programs in the developing limb.
  35. Causal inference in medical records and complementary systems pharmacology for metformin drug repurposing towards dementia.
  36. Hepatic neddylation deficiency triggers fatal liver injury via inducing NF-κB-inducing kinase in mice.
  37. Lipopolysaccharide Primes Human Macrophages for Noncanonical Inflammasome-Induced Extracellular Vesicle Secretion.
  38. A multiple sclerosis-protective coding variant reveals an essential role for HDAC7 in regulatory T cells.
  39. Caspase-8 activation in neutrophils facilitates autoimmune kidney vasculitis through regulating CD4+ effector memory T cells.
  40. TIGIT inhibition and lenalidomide synergistically promote anti-myeloma immune responses after stem cell transplantation in mice.
  41. An atlas of late prenatal human neurodevelopment resolved by single-nucleus transcriptomics.
  42. Synthetic cytokine circuits that drive T cells into immune-excluded tumors.
  43. "Off-the-Shelf" CAR T-Cell Therapy Tested in Pediatric B-Cell Leukemia.
  44. RSV wave hammers hospitals - but vaccines and treatments are coming.
  45. Brain metastatic outgrowth and osimertinib resistance are potentiated by RhoA in EGFR-mutant lung cancer.
  46. Autophagy inducer rapamycin treatment reduces IFN-I-mediated Inflammation and improves anti-HIV-1 T cell response in vivo.
  47. Glucose- and glutamine-dependent bioenergetics sensitize bone mechanoresponse after unloading by modulating osteocyte calcium dynamics.
  48. Activated cholesterol metabolism is integral for innate macrophage responses by amplifying Myd88 signaling.
  49. Species-specific rewiring of definitive endoderm developmental gene activation via endogenous retroviruses through TET1-mediated demethylation.
  50. Recruited monocytes/macrophages drive pulmonary neutrophilic inflammation and irreversible lung tissue remodeling in cystic fibrosis.
  51. Spatial transcriptomics landscape of lesions from non-communicable inflammatory skin diseases.
  52. Regulation of bone homeostasis by MERTK and TYRO3.
  53. Delivery of costimulatory blockade to lymph nodes promotes transplant acceptance in mice.
  54. Structure of nucleosome-bound human PBAF complex.
  55. Mechanistic insight into female predominance in Alzheimer's disease based on aberrant protein S-nitrosylation of C3.
  56. Stage-specific and cell type-specific requirements of ikzf1 during haematopoietic differentiation in zebrafish.
  57. A rapid RIG-I signaling relay mediates efficient antiviral response.
  58. Ovarian cancer mutational processes drive site-specific immune evasion.
  59. Single-cell analysis of senescent epithelia reveals targetable mechanisms promoting fibrosis.
  60. Phenome-wide association study of loci harboring de novo tandem repeat mutations in UK Biobank exomes.
  61. Condensates formed by prion-like low-complexity domains have small-world network structures and interfaces defined by expanded conformations.
  1. Nat Immunol. 2022 Dec 15.
    A genetic disorder reveals a hematopoietic stem cell regulatory network co-opted in leukemia.
    Richard A Voit, Liming Tao, Fulong Yu, Liam D Cato, Blake Cohen, Travis J Fleming, Mateusz Antoszewski, Xiaotian Liao, Claudia Fiorini, Satish K Nandakumar, Lara Wahlster, Kristian Teichert, Aviv Regev, Vijay G Sankaran.
      The molecular regulation of human hematopoietic stem cell (HSC) maintenance is therapeutically important, but limitations in experimental systems and interspecies variation have constrained our knowledge of this process. Here, we have studied a rare genetic disorder due to MECOM haploinsufficiency, characterized by an early-onset absence of HSCs in vivo. By generating a faithful model of this disorder in primary human HSCs and coupling functional studies with integrative single-cell genomic analyses, we uncover a key transcriptional network involving hundreds of genes that is required for HSC maintenance. Through our analyses, we nominate cooperating transcriptional regulators and identify how MECOM prevents the CTCF-dependent genome reorganization that occurs as HSCs differentiate. We show that this transcriptional network is co-opted in high-risk leukemias, thereby enabling these cancers to acquire stem cell properties. Collectively, we illuminate a regulatory network necessary for HSC self-renewal through the study of a rare experiment of nature.
    DOI:  https://doi.org/10.1038/s41590-022-01370-4
  2. Nat Commun. 2022 Dec 10. 13(1): 7637
    Mitochondrial dysfunction induces ALK5-SMAD2-mediated hypovascularization and arteriovenous malformations in mouse retinas.
    Haifeng Zhang, Busu Li, Qunhua Huang, Francesc López-Giráldez, Yoshiaki Tanaka, Qun Lin, Sameet Mehta, Guilin Wang, Morven Graham, Xinran Liu, In-Hyun Park, Anne Eichmann, Wang Min, Jenny Huanjiao Zhou.
      Although mitochondrial activity is critical for angiogenesis, its mechanism is not entirely clear. Here we show that mice with endothelial deficiency of any one of the three nuclear genes encoding for mitochondrial proteins, transcriptional factor (TFAM), respiratory complex IV component (COX10), or redox protein thioredoxin 2 (TRX2), exhibit retarded retinal vessel growth and arteriovenous malformations (AVM). Single-cell RNA-seq analyses indicate that retinal ECs from the three mutant mice have increased TGFβ signaling and altered gene expressions associated with vascular maturation and extracellular matrix, correlating with vascular malformation and increased basement membrane thickening in microvesels of mutant retinas. Mechanistic studies suggest that mitochondrial dysfunction from Tfam, Cox10, or Trx2 depletion induces a mitochondrial localization and MAPKs-mediated phosphorylation of SMAD2, leading to enhanced ALK5-SMAD2 signaling. Importantly, pharmacological blockade of ALK5 signaling or genetic deficiency of SMAD2 prevented retinal vessel growth retardation and AVM in all three mutant mice. Our studies uncover a novel mechanism whereby mitochondrial dysfunction via the ALK5-SMAD2 signaling induces retinal vascular malformations, and have therapeutic values for the alleviation of angiogenesis-associated human retinal diseases.
    DOI:  https://doi.org/10.1038/s41467-022-35262-w
  3. Nat Commun. 2022 Dec 10. 13(1): 7633
    A brown fat-enriched adipokine Adissp controls adipose thermogenesis and glucose homeostasis.
    Qingbo Chen, Lei Huang, Dongning Pan, Kai Hu, Rui Li, Randall H Friedline, Jason K Kim, Lihua Julie Zhu, David A Guertin, Yong-Xu Wang.
      The signaling mechanisms underlying adipose thermogenesis have not been fully elucidated. Particularly, the involvement of adipokines that are selectively expressed in brown adipose tissue (BAT) and beige adipocytes remains to be investigated. Here we show that a previously uncharacterized adipokine (UPF0687 protein / human C20orf27 homolog) we named as Adissp (Adipose-secreted signaling protein) is a key regulator for white adipose tissue (WAT) thermogenesis and glucose homeostasis. Adissp expression is adipose-specific and highly BAT-enriched, and its secretion is stimulated by β3-adrenergic activation. Gain-of-functional studies collectively showed that secreted Adissp promotes WAT thermogenesis, improves glucose homeostasis, and protects against obesity. Adipose-specific Adissp knockout mice are defective in WAT browning, and are susceptible to high fat diet-induced obesity and hyperglycemia. Mechanistically, Adissp binds to a putative receptor on adipocyte surface and activates protein kinase A independently of β-adrenergic signaling. These results establish BAT-enriched Adissp as a major upstream signaling component in thermogenesis and offer a potential avenue for the treatment of obesity and diabetes.
    DOI:  https://doi.org/10.1038/s41467-022-35335-w
  4. Science. 2022 Dec 16. 378(6625): eadf3971
    Protein import into peroxisomes occurs through a nuclear pore-like phase.
    Yuan Gao, Michael L Skowyra, Peiqiang Feng, Tom A Rapoport.
      Peroxisomes are ubiquitous organelles whose dysfunction causes fatal human diseases. Most peroxisomal proteins are imported from the cytosol in a folded state by the soluble receptor PEX5. How folded cargo crosses the membrane is unknown. Here, we show that peroxisomal import is similar to nuclear transport. The peroxisomal membrane protein PEX13 contains a conserved tyrosine (Y)- and glycine (G)-rich YG domain, which forms a selective phase resembling that formed by phenylalanine-glycine (FG) repeats within nuclear pores. PEX13 resides in the membrane in two orientations that oligomerize and suspend the YG meshwork within the lipid bilayer. Purified YG domains form hydrogels into which PEX5 selectively partitions, by using conserved aromatic amino acid motifs, bringing cargo along. The YG meshwork thus forms an aqueous conduit through which PEX5 delivers folded proteins into peroxisomes.
    DOI:  https://doi.org/10.1126/science.adf3971
  5. J Clin Invest. 2022 Dec 15. pii: e165620. [Epub ahead of print]132(24):
    A humanized mouse model to study NK cell biology during HIV infection.
    Jocelyn T Kim, Jerome A Zack.
      NK cells are an important subset of innate immune effectors with antiviral activity. However, NK cell development and immune responses in different tissues during acute and chronic HIV infection in vivo have been difficult to study due to the impaired development and function of NK cells in conventional humanized mouse models. In this issue of the JCI, Sangur et al. report on a transgenic MISTRG-6-15 mouse model with human IL-6 and IL-15 knocked into the previously constructed MISTRG mice. The predecessor model was deficient in Rag2 and γ chain (γc) with knock-in expression of human M-CSF, IL-3, GM-CSF, and TPO, and transgenic expression of human SIRPα. The researchers studied tissue-specific NK cell immune responses during HIV infection and clearly show that the endogenous human NK cells in the humanized mouse model suppressed HIV-1 replication in vivo. These findings provide insight into harnessing the innate immune response for clinical antiviral therapies.
    DOI:  https://doi.org/10.1172/JCI165620
  6. Nat Commun. 2022 Dec 10. 13(1): 7657
    Myeloid cells promote interferon signaling-associated deterioration of the hematopoietic system.
    Jacqueline Feyen, Zhen Ping, Lanpeng Chen, Claire van Dijk, Tim V D van Tienhoven, Paulina M H van Strien, Remco M Hoogenboezem, Michiel J W Wevers, Mathijs A Sanders, Ivo P Touw, Marc H G P Raaijmakers.
      Innate and adaptive immune cells participate in the homeostatic regulation of hematopoietic stem cells (HSCs). Here, we interrogate the contribution of myeloid cells, the most abundant cell type in the mammalian bone marrow, in a clinically relevant mouse model of neutropenia. Long-term genetic depletion of neutrophils and eosinophils results in activation of multipotent progenitors but preservation of HSCs. Depletion of myeloid cells abrogates HSC expansion, loss of serial repopulation and lymphoid reconstitution capacity and remodeling of HSC niches, features previously associated with hematopoietic aging. This is associated with mitigation of interferon signaling in both HSCs and their niches via reduction of NK cell number and activation. These data implicate myeloid cells in the functional decline of hematopoiesis, associated with activation of interferon signaling via a putative neutrophil-NK cell axis. Innate immunity may thus come at the cost of system deterioration through enhanced chronic inflammatory signaling to stem cells and their niches.
    DOI:  https://doi.org/10.1038/s41467-022-35318-x
  7. Nat Commun. 2022 Dec 10. 13(1): 7656
    A glutamate receptor C-tail recruits CaMKII to suppress retrograde homeostatic signaling.
    Sarah Perry, Yifu Han, Chengjie Qiu, Chun Chien, Pragya Goel, Samantha Nishimura, Manisha Sajnani, Andreas Schmid, Stephan J Sigrist, Dion Dickman.
      Presynaptic homeostatic plasticity (PHP) adaptively enhances neurotransmitter release following diminished postsynaptic glutamate receptor (GluR) functionality to maintain synaptic strength. While much is known about PHP expression mechanisms, postsynaptic induction remains enigmatic. For over 20 years, diminished postsynaptic Ca2+ influx was hypothesized to reduce CaMKII activity and enable retrograde PHP signaling at the Drosophila neuromuscular junction. Here, we have interrogated inductive signaling and find that active CaMKII colocalizes with and requires the GluRIIA receptor subunit. Next, we generated Ca2+-impermeable GluRs to reveal that both CaMKII activity and PHP induction are Ca2+-insensitive. Rather, a GluRIIA C-tail domain is necessary and sufficient to recruit active CaMKII. Finally, chimeric receptors demonstrate that the GluRIIA tail constitutively occludes retrograde homeostatic signaling by stabilizing active CaMKII. Thus, the physical loss of the GluRIIA tail is sensed, rather than reduced Ca2+, to enable retrograde PHP signaling, highlighting a unique, Ca2+-independent control mechanism for CaMKII in gating homeostatic plasticity.
    DOI:  https://doi.org/10.1038/s41467-022-35417-9
  8. Nat Commun. 2022 Dec 13. 13(1): 7703
    Locally organised and activated Fth1hi neutrophils aggravate inflammation of acute lung injury in an IL-10-dependent manner.
    Kun Wang, Muyun Wang, Ximing Liao, Shaoyong Gao, Jing Hua, Xiaodong Wu, Qian Guo, Wujian Xu, Jiaxing Sun, Yanan He, Qiang Li, Wei Gao.
      Acute respiratory distress syndrome (ARDS) is a common respiratory critical syndrome with no effective therapeutic intervention. Neutrophils function in the overwhelming inflammatory process of acute lung injury (ALI) caused by ARDS; however, the phenotypic heterogeneity of pulmonary neutrophils in ALI/ARDS remains largely unknown. Here, using single-cell RNA sequencing, we identify two transcriptionally and functionally heterogeneous neutrophil populations (Fth1hi Neu and Prok2hi Neu) with distinct locations in LPS-induced ALI mouse lungs. Exposure to LPS promotes the Fth1hi Neu subtype, with more inflammatory factors, stronger antioxidant, and decreased apoptosis under the regulation of interleukin-10. Furthermore, prolonged retention of Fth1hi Neu within lung tissue aggravates inflammatory injury throughout the development of ALI/ARDS. Notably, ARDS patients have high ratios of Fth1 to Prok2 expression in pulmonary neutrophils, suggesting that the Fth1hi Neu population may promote the pathological development and provide a marker of poor outcome.
    DOI:  https://doi.org/10.1038/s41467-022-35492-y
  9. Nat Commun. 2022 Dec 10. 13(1): 7640
    Spatial-ID: a cell typing method for spatially resolved transcriptomics via transfer learning and spatial embedding.
    Rongbo Shen, Lin Liu, Zihan Wu, Ying Zhang, Zhiyuan Yuan, Junfu Guo, Fan Yang, Chao Zhang, Bichao Chen, Wanwan Feng, Chao Liu, Jing Guo, Guozhen Fan, Yong Zhang, Yuxiang Li, Xun Xu, Jianhua Yao.
      Spatially resolved transcriptomics provides the opportunity to investigate the gene expression profiles and the spatial context of cells in naive state, but at low transcript detection sensitivity or with limited gene throughput. Comprehensive annotating of cell types in spatially resolved transcriptomics to understand biological processes at the single cell level remains challenging. Here we propose Spatial-ID, a supervision-based cell typing method, that combines the existing knowledge of reference single-cell RNA-seq data and the spatial information of spatially resolved transcriptomics data. We present a series of benchmarking analyses on publicly available spatially resolved transcriptomics datasets, that demonstrate the superiority of Spatial-ID compared with state-of-the-art methods. Besides, we apply Spatial-ID on a self-collected mouse brain hemisphere dataset measured by Stereo-seq, that shows the scalability of Spatial-ID to three-dimensional large field tissues with subcellular spatial resolution.
    DOI:  https://doi.org/10.1038/s41467-022-35288-0
  10. Nat Genet. 2022 Dec 15.
    Human genetic diversity alters off-target outcomes of therapeutic gene editing.
    Samuele Cancellieri, Jing Zeng, Linda Yingqi Lin, Manuel Tognon, My Anh Nguyen, Jiecong Lin, Nicola Bombieri, Stacy A Maitland, Marioara-Felicia Ciuculescu, Varun Katta, Shengdar Q Tsai, Myriam Armant, Scot A Wolfe, Rosalba Giugno, Daniel E Bauer, Luca Pinello.
      CRISPR gene editing holds great promise to modify DNA sequences in somatic cells to treat disease. However, standard computational and biochemical methods to predict off-target potential focus on reference genomes. We developed an efficient tool called CRISPRme that considers single-nucleotide polymorphism (SNP) and indel genetic variants to nominate and prioritize off-target sites. We tested the software with a BCL11A enhancer targeting guide RNA (gRNA) showing promise in clinical trials for sickle cell disease and β-thalassemia and found that the top candidate off-target is produced by an allele common in African-ancestry populations (MAF 4.5%) that introduces a protospacer adjacent motif (PAM) sequence. We validated that SpCas9 generates strictly allele-specific indels and pericentric inversions in CD34+ hematopoietic stem and progenitor cells (HSPCs), although high-fidelity Cas9 mitigates this off-target. This report illustrates how genetic variants should be considered as modifiers of gene editing outcomes. We expect that variant-aware off-target assessment will become integral to therapeutic genome editing evaluation and provide a powerful approach for comprehensive off-target nomination.
    DOI:  https://doi.org/10.1038/s41588-022-01257-y
  11. Immunity. 2022 Dec 09. pii: S1074-7613(22)00603-3. [Epub ahead of print]
    Prolonged hypernutrition impairs TREM2-dependent efferocytosis to license chronic liver inflammation and NASH development.
    Xiaochen Wang, Qifeng He, Chuanli Zhou, Yueyuan Xu, Danhui Liu, Naoto Fujiwara, Naoto Kubota, Arielle Click, Polly Henderson, Janiece Vancil, Cesia Ammi Marquez, Ganesh Gunasekaran, Myron E Schwartz, Parissa Tabrizian, Umut Sarpel, Maria Isabel Fiel, Yarui Diao, Beicheng Sun, Yujin Hoshida, Shuang Liang, Zhenyu Zhong.
      Obesity-induced chronic liver inflammation is a hallmark of nonalcoholic steatohepatitis (NASH)-an aggressive form of nonalcoholic fatty liver disease. However, it remains unclear how such a low-grade, yet persistent, inflammation is sustained in the liver. Here, we show that the macrophage phagocytic receptor TREM2, induced by hepatocyte-derived sphingosine-1-phosphate, was required for efferocytosis of lipid-laden apoptotic hepatocytes and thereby maintained liver immune homeostasis. However, prolonged hypernutrition led to the production of proinflammatory cytokines TNF and IL-1β in the liver to induce TREM2 shedding through ADAM17-dependent proteolytic cleavage. Loss of TREM2 resulted in aberrant accumulation of dying hepatocytes, thereby further augmenting proinflammatory cytokine production. This ultimately precipitated a vicious cycle that licensed chronic inflammation to drive simple steatosis transition to NASH. Therefore, impaired macrophage efferocytosis is a previously unrecognized key pathogenic event that enables chronic liver inflammation in obesity. Blocking TREM2 cleavage to restore efferocytosis may represent an effective strategy to treat NASH.
    Keywords:  TREM2; chronic inflammation; efferocytosis; nonalcoholic steatohepatitis; proinflammatory cytokines
    DOI:  https://doi.org/10.1016/j.immuni.2022.11.013
  12. Cell. 2022 Dec 07. pii: S0092-8674(22)01463-5. [Epub ahead of print]
    Cerebrospinal fluid immune dysregulation during healthy brain aging and cognitive impairment.
    Natalie Piehl, Lynn van Olst, Abhirami Ramakrishnan, Victoria Teregulova, Brooke Simonton, Ziyang Zhang, Emma Tapp, Divya Channappa, Hamilton Oh, Patricia M Losada, Jarod Rutledge, Alexandra N Trelle, Elizabeth C Mormino, Fanny Elahi, Douglas R Galasko, Victor W Henderson, Anthony D Wagner, Tony Wyss-Coray, David Gate.
      Cerebrospinal fluid (CSF) contains a tightly regulated immune system. However, knowledge is lacking about how CSF immunity is altered with aging or neurodegenerative disease. Here, we performed single-cell RNA sequencing on CSF from 45 cognitively normal subjects ranging from 54 to 82 years old. We uncovered an upregulation of lipid transport genes in monocytes with age. We then compared this cohort with 14 cognitively impaired subjects. In cognitively impaired subjects, downregulation of lipid transport genes in monocytes occurred concomitantly with altered cytokine signaling to CD8 T cells. Clonal CD8 T effector memory cells upregulated C-X-C motif chemokine receptor 6 (CXCR6) in cognitively impaired subjects. The CXCR6 ligand, C-X-C motif chemokine ligand 16 (CXCL16), was elevated in the CSF of cognitively impaired subjects, suggesting CXCL16-CXCR6 signaling as a mechanism for antigen-specific T cell entry into the brain. Cumulatively, these results reveal cerebrospinal fluid immune dysregulation during healthy brain aging and cognitive impairment.
    Keywords:  Alzheimer's disease; T cells; adaptive immunity; aging; cerebrospinal fluid; cognitive impairment
    DOI:  https://doi.org/10.1016/j.cell.2022.11.019
  13. Nat Commun. 2022 Dec 17. 13(1): 7792
    Muscle 4EBP1 activation modifies the structure and function of the neuromuscular junction in mice.
    Seok-Ting J Ang, Elisa M Crombie, Han Dong, Kuan-Ting Tan, Adriel Hernando, Dejie Yu, Stuart Adamson, Seonyoung Kim, Dominic J Withers, Hua Huang, Shih-Yin Tsai.
      Dysregulation of mTOR complex 1 (mTORC1) activity drives neuromuscular junction (NMJ) structural instability during aging; however, downstream targets mediating this effect have not been elucidated. Here, we investigate the roles of two mTORC1 phosphorylation targets for mRNA translation, ribosome protein S6 kinase 1 (S6K1) and eukaryotic translation initiation factor 4E-binding protein 1 (4EBP1), in regulating NMJ structural instability induced by aging and sustained mTORC1 activation. While myofiber-specific deletion of S6k1 has no effect on NMJ structural integrity, 4EBP1 activation in murine muscle induces drastic morphological remodeling of the NMJ with enhancement of synaptic transmission. Mechanistically, structural modification of the NMJ is attributed to increased satellite cell activation and enhanced post-synaptic acetylcholine receptor (AChR) turnover upon 4EBP1 activation. Considering that loss of post-synaptic myonuclei and reduced NMJ turnover are features of aging, targeting 4EBP1 activation could induce NMJ renewal by expanding the pool of post-synaptic myonuclei as an alternative intervention to mitigate sarcopenia.
    DOI:  https://doi.org/10.1038/s41467-022-35547-0
  14. Nat Commun. 2022 Dec 13. 13(1): 7715
    Upper gut heat shock proteins HSP70 and GRP78 promote insulin resistance, hyperglycemia, and non-alcoholic steatohepatitis.
    Giulia Angelini, Lidia Castagneto-Gissey, Serenella Salinari, Alessandro Bertuzzi, Danila Anello, Meenakshi Pradhan, Marlen Zschätzsch, Paul Ritter, Carel W Le Roux, Francesco Rubino, Nicola Basso, Giovanni Casella, Stefan R Bornstein, Valentina Tremaroli, Geltrude Mingrone.
      A high-fat diet increases the risk of insulin resistance, type-2 diabetes, and non-alcoholic steato-hepatitis. Here we identified two heat-shock proteins, Heat-Shock-Protein70 and Glucose-Regulated Protein78, which are increased in the jejunum of rats on a high-fat diet. We demonstrated a causal link between these proteins and hepatic and whole-body insulin-resistance, as well as the metabolic response to bariatric/metabolic surgery. Long-term continuous infusion of Heat-Shock-Protein70 and Glucose-Regulated Protein78 caused insulin-resistance, hyperglycemia, and non-alcoholic steato-hepatitis in rats on a chow diet, while in rats on a high-fat diet continuous infusion of monoclonal antibodies reversed these phenotypes, mimicking metabolic surgery. Infusion of these proteins or their antibodies was also associated with shifts in fecal microbiota composition. Serum levels of Heat-Shock-Protein70 and Glucose-Regulated Protein78were elevated in patients with non-alcoholic steato-hepatitis, but decreased following metabolic surgery. Understanding the intestinal regulation of metabolism may provide options to reverse metabolic diseases.
    DOI:  https://doi.org/10.1038/s41467-022-35310-5
  15. Mol Cell. 2022 Dec 08. pii: S1097-2765(22)01130-3. [Epub ahead of print]
    Macrophage inflammatory and regenerative response periodicity is programmed by cell cycle and chromatin state.
    Bence Daniel, Julia A Belk, Stefanie L Meier, Andy Y Chen, Katalin Sandor, Zsolt Czimmerer, Zsofia Varga, Krisztian Bene, Frank A Buquicchio, Yanyan Qi, Hugo Kitano, Joshua R Wheeler, Deshka S Foster, Michael Januszyk, Michael T Longaker, Howard Y Chang, Ansuman T Satpathy.
      Cell cycle (CC) facilitates cell division via robust, cyclical gene expression. Protective immunity requires the expansion of pathogen-responsive cell types, but whether CC confers unique gene expression programs that direct the subsequent immunological response remains unclear. Here, we demonstrate that single macrophages (MFs) adopt different plasticity states in CC, which leads to heterogeneous cytokine-induced polarization, priming, and repolarization programs. Specifically, MF plasticity to interferon gamma (IFNG) is substantially reduced during S-G2/M, whereas interleukin 4 (IL-4) induces S-G2/M-biased gene expression, mediated by CC-biased enhancers. Additionally, IL-4 polarization shifts the CC-phase distribution of MFs toward the G2/M phase, providing a subpopulation-specific mechanism for IL-4-induced, dampened IFNG responsiveness. Finally, we demonstrate CC-dependent MF responses in murine and human disease settings in vivo, including Th2-driven airway inflammation and pulmonary fibrosis, where MFs express an S-G2/M-biased tissue remodeling gene program. Therefore, MF inflammatory and regenerative responses are gated by CC in a cyclical, phase-dependent manner.
    Keywords:  cell cycle; macrophage plasticity; macrophage polarization; single-cell epigenomics
    DOI:  https://doi.org/10.1016/j.molcel.2022.11.017
  16. Nat Commun. 2022 Dec 10. 13(1): 7648
    Targeting cardiomyocyte ADAM10 ectodomain shedding promotes survival early after myocardial infarction.
    Erik Klapproth, Anke Witt, Pauline Klose, Johanna Wiedemann, Nikitha Vavilthota, Stephan R Künzel, Susanne Kämmerer, Mario Günscht, David Sprott, Mathias Lesche, Fabian Rost, Andreas Dahl, Erik Rauch, Lars Kattner, Silvio Weber, Peter Mirtschink, Irakli Kopaliani, Kaomei Guan, Kristina Lorenz, Paul Saftig, Michael Wagner, Ali El-Armouche.
      After myocardial infarction the innate immune response is pivotal in clearing of tissue debris as well as scar formation, but exaggerated cytokine and chemokine secretion with subsequent leukocyte infiltration also leads to further tissue damage. Here, we address the value of targeting a previously unknown a disintegrin and metalloprotease 10 (ADAM10)/CX3CL1 axis in the regulation of neutrophil recruitment early after MI. We show that myocardial ADAM10 is distinctly upregulated in myocardial biopsies from patients with ischemia-driven cardiomyopathy. Intriguingly, upon MI in mice, pharmacological ADAM10 inhibition as well as genetic cardiomycyte-specific ADAM10 deletion improves survival with markedly enhanced heart function and reduced scar size. Mechanistically, abolished ADAM10-mediated CX3CL1 ectodomain shedding leads to diminished IL-1β-dependent inflammation, reduced neutrophil bone marrow egress as well as myocardial tissue infiltration. Thus, our data shows a conceptual insight into how acute MI induces chemotactic signaling via ectodomain shedding in cardiomyocytes.
    DOI:  https://doi.org/10.1038/s41467-022-35331-0
  17. Commun Biol. 2022 Dec 13. 5(1): 1366
    Neutrophil trafficking to the site of infection requires Cpt1a-dependent fatty acid β-oxidation.
    Ly Pham, Padmini Komalavilas, Alex M Eddie, Timothy E Thayer, Dalton L Greenwood, Ken H Liu, Jaclyn Weinberg, Andrew Patterson, Joshua P Fessel, Kelli L Boyd, Jenny C Schafer, Jamie L Kuck, Aaron C Shaver, David K Flaherty, Brittany K Matlock, Christiaan D M Wijers, C Henrique Serezani, Dean P Jones, Evan L Brittain, Jeffrey C Rathmell, Michael J Noto.
      Cellular metabolism influences immune cell function, with mitochondrial fatty acid β-oxidation and oxidative phosphorylation required for multiple immune cell phenotypes. Carnitine palmitoyltransferase 1a (Cpt1a) is considered the rate-limiting enzyme for mitochondrial metabolism of long-chain fatty acids, and Cpt1a deficiency is associated with infant mortality and infection risk. This study was undertaken to test the hypothesis that impairment in Cpt1a-dependent fatty acid oxidation results in increased susceptibility to infection. Screening the Cpt1a gene for common variants predicted to affect protein function revealed allele rs2229738_T, which was associated with pneumonia risk in a targeted human phenome association study. Pharmacologic inhibition of Cpt1a increases mortality and impairs control of the infection in a murine model of bacterial pneumonia. Susceptibility to pneumonia is associated with blunted neutrophilic responses in mice and humans that result from impaired neutrophil trafficking to the site of infection. Chemotaxis responsible for neutrophil trafficking requires Cpt1a-dependent mitochondrial fatty acid oxidation for amplification of chemoattractant signals. These findings identify Cpt1a as a potential host determinant of infection susceptibility and demonstrate a requirement for mitochondrial fatty acid oxidation in neutrophil biology.
    DOI:  https://doi.org/10.1038/s42003-022-04339-z
  18. J Clin Invest. 2022 Dec 13. pii: e156722. [Epub ahead of print]
    LepRb cell-specific deletion of Slug mitigates obesity and NAFLD.
    Min-Hyun Kim, Yuan Li, Qiantao Zheng, Lin Jiang, Martin G Myers, Wen-Shu Wu, Liangyou Rui.
      Leptin exerts its biological actions by activating LepRb. LepRb signaling impairment and leptin resistance are believed to cause obesity. Transcription factor Slug (also known as Snai2) recruits epigenetic modifiers and regulates gene expression by an epigenetic mechanism; however, its epigenetic action has not been explored in leptin resistance. Here, we uncover a pro-obesity function of neuronal Slug. Hypothalamic Slug was upregulated in obese mice. LepRb cell-specific Slug knockout (SlugΔLepRb) mice were resistant to diet-induced obesity, type 2 diabetes, and liver steatosis, accompanied by decreased food intake and increased fat thermogenesis. Leptin stimulated hypothalamic Stat3 phosphorylation and weight loss to a significantly higher level in SlugΔLepRb than in Slugf/f mice even before their body weight divergence. Conversely, hypothalamic LepRb neuron-specific overexpression of Slug, mediated by AAV-DIO-Slug transduction, induced leptin resistance, obesity, and metabolic disorders in mice on a chow diet. At the genomic level, Slug bound to and repressed the LepRb promoter, thereby inhibiting LepRb transcription. Consistently, Slug deficiency decreased LepRb promoter histone 3 lysine-27 methylations, repressive epigenetic marks, and increased LepRb mRNA levels in the hypothalamus. Collectively, these results unravel a previously-unrecognized hypothalamic neuronal Slug/epigenetic reprogramming/leptin resistance axis that promotes energy imbalance, obesity, and metabolic disease.
    Keywords:  Cell Biology; Diabetes; Leptin; Metabolism; Obesity
    DOI:  https://doi.org/10.1172/JCI156722
  19. Nat Immunol. 2022 Dec 12.
    Aging-associated HELIOS deficiency in naive CD4+ T cells alters chromatin remodeling and promotes effector cell responses.
    Huimin Zhang, Rohit R Jadhav, Wenqiang Cao, Isabel N Goronzy, Tuantuan V Zhao, Jun Jin, Shozo Ohtsuki, Zhaolan Hu, Jose Morales, William J Greenleaf, Cornelia M Weyand, Jörg J Goronzy.
      Immune aging combines cellular defects in adaptive immunity with the activation of pathways causing a low-inflammatory state. Here we examined the influence of age on the kinetic changes in the epigenomic and transcriptional landscape induced by T cell receptor (TCR) stimulation in naive CD4+ T cells. Despite attenuated TCR signaling in older adults, TCR activation accelerated remodeling of the epigenome and induced transcription factor networks favoring effector cell differentiation. We identified increased phosphorylation of STAT5, at least in part due to aberrant IL-2 receptor and lower HELIOS expression, as upstream regulators. Human HELIOS-deficient, naive CD4+ T cells, when transferred into human-synovium-mouse chimeras, infiltrated tissues more efficiently. Inhibition of IL-2 or STAT5 activity in T cell responses of older adults restored the epigenetic response pattern to the one seen in young adults. In summary, reduced HELIOS expression in non-regulatory naive CD4+ T cells in older adults directs T cell fate decisions toward inflammatory effector cells that infiltrate tissue.
    DOI:  https://doi.org/10.1038/s41590-022-01369-x
  20. Immunity. 2022 Dec 13. pii: S1074-7613(22)00600-8. [Epub ahead of print]55(12): 2225-2227
    IRF2 integrates inflammatory signals to balance T cell exhaustion.
    Amania A Sheikh, Daniel T Utzschneider.
      The transcription factor interferon regulatory factor 2 (IRF2) translates interferon signaling to regulate T cells. In this issue of Immunity, Lukhele et al. identify IRF2 in tumor-infiltrating T cells as a sensor for extrinsic signals that drives an exhaustion program.
    DOI:  https://doi.org/10.1016/j.immuni.2022.11.010
  21. Nat Commun. 2022 Dec 10. 13(1): 7658
    Sirt6 attenuates chondrocyte senescence and osteoarthritis progression.
    Ming-Liang Ji, Hua Jiang, Zhuang Li, Rui Geng, Jun Zheng Hu, Yu Cheng Lin, Jun Lu.
      Sirt6 has been implicated as a key regulator in aging-related diseases, including osteoarthritis. However, its functional role and molecular mechanism in chondrocyte senescence and osteoarthritis pathophysiology remain largely undefined. Here we show that Sirt6 deficiency exaggerates chondrocyte senescence and osteoarthritis progression, whereas intra-articular injection of adenovirus-Sirt6 markedly attenuates surgical destabilization of medial meniscus-induced osteoarthritis. Mechanistically, Sirt6 can directly interact with STAT5 and deacetylate STAT5, thus inhibiting the IL-15/JAK3-induced STAT5 translocation from cytoplasm to nucleus, which inactivates IL-15/JAK3/STAT5 signaling. Mass spectrometry revealed that Sirt6 deacetylated conserved lysine 163 on STAT5. Mutation of lysine 163 to arginine in STAT5 abolished the regulatory effect of Sirt6. In vivo, specific ablation of Sirt6 in chondrocytes exacerbated osteoarthritis. Pharmacological activation of Sirt6 substantially alleviated chondrocyte senescence. Taken together, Sirt6 attenuates chondrocyte senescence by inhibiting IL-15/JAK3/STAT5 signaling. Targeting Sirt6 represents a promising new approach for osteoarthritis.
    DOI:  https://doi.org/10.1038/s41467-022-35424-w
  22. Nat Commun. 2022 Dec 13. 13(1): 7700
    Finger-palm synergistic soft gripper for dynamic capture via energy harvesting and dissipation.
    Yin Zhang, Wang Zhang, Pan Gao, Xiaoqing Zhong, Wei Pu.
      Robotic grippers, inspired by human hands, show an extraordinary ability to manipulate objects of various shapes, sizes, or materials. However, capturing objects with varying kinetic energy remains challenging, regardless of the classical rigid-bodied or frontier soft-bodied grippers. Here, we demonstrate a rapid energy harvesting and dissipation mechanism for the soft grippers leveraging the finger-palm synergy. Theoretically and experimentally, this mechanism enables a soft gripper to reliably capture high-speed targets by dissipating and harvesting almost all the target's kinetic energy within 30 milliseconds. The energy harvesting and dissipating capability are adjustable and can be enhanced by inflating pressure. Additionally, the harvested energy is autonomously transferred into fingers to enhance their grasping force and reduce the response time. To highlight, the grippers we developed are integrated into a six-rotor drone and successfully capture flying objects in an outdoor experiment. These results significantly advance robotics development in achieving dynamic capture of dynamic targets.
    DOI:  https://doi.org/10.1038/s41467-022-35479-9
  23. Sci Adv. 2022 Dec 16. 8(50): eabo4082
    Widespread transposon co-option in the Caenorhabditis germline regulatory network.
    Francesco Nicola Carelli, Chiara Cerrato, Yan Dong, Alex Appert, Abby Dernburg, Julie Ahringer.
      The movement of selfish DNA elements can lead to widespread genomic alterations with potential to create novel functions. We show that transposon expansions in Caenorhabditis nematodes led to extensive rewiring of germline transcriptional regulation. We find that about one-third of Caenorhabditis elegans germline-specific promoters have been co-opted from two related miniature inverted repeat transposable elements (TEs), CERP2 and CELE2. These promoters are regulated by HIM-17, a THAP domain-containing transcription factor related to a transposase. Expansion of CERP2 occurred before radiation of the Caenorhabditis genus, as did fixation of mutations in HIM-17 through positive selection, whereas CELE2 expanded only in C. elegans. Through comparative analyses in Caenorhabditis briggsae, we find not only evolutionary conservation of most CERP2 co-opted promoters but also a substantial fraction that are species-specific. Our work reveals the emergence and evolutionary conservation of a novel transcriptional network driven by TE co-option with a major impact on regulatory evolution.
    DOI:  https://doi.org/10.1126/sciadv.abo4082
  24. J Exp Med. 2023 Feb 06. pii: e20220275. [Epub ahead of print]220(2):
    Human CARMIL2 deficiency underlies a broader immunological and clinical phenotype than CD28 deficiency.
    CARMIL2 Consortium
      Patients with inherited CARMIL2 or CD28 deficiency have defective T cell CD28 signaling, but their immunological and clinical phenotypes remain largely unknown. We show that only one of three CARMIL2 isoforms is produced and functional across leukocyte subsets. Tested mutant CARMIL2 alleles from 89 patients and 52 families impair canonical NF-κB but not AP-1 and NFAT activation in T cells stimulated via CD28. Like CD28-deficient patients, CARMIL2-deficient patients display recalcitrant warts and low blood counts of CD4+ and CD8+ memory T cells and CD4+ TREGs. Unlike CD28-deficient patients, they have low counts of NK cells and memory B cells, and their antibody responses are weak. CARMIL2 deficiency is fully penetrant by the age of 10 yr and is characterized by numerous infections, EBV+ smooth muscle tumors, and mucocutaneous inflammation, including inflammatory bowel disease. Patients with somatic reversions of a mutant allele in CD4+ T cells have milder phenotypes. Our study suggests that CARMIL2 governs immunological pathways beyond CD28.
    DOI:  https://doi.org/10.1084/jem.20220275
  25. Nat Commun. 2022 Dec 12. 13(1): 7439
    SIRT7 suppresses energy expenditure and thermogenesis by regulating brown adipose tissue functions in mice.
    Tatsuya Yoshizawa, Yoshifumi Sato, Shihab U Sobuz, Tomoya Mizumoto, Tomonori Tsuyama, Md Fazlul Karim, Keishi Miyata, Masayoshi Tasaki, Masaya Yamazaki, Yuichi Kariba, Norie Araki, Eiichi Araki, Shingo Kajimura, Yuichi Oike, Thomas Braun, Eva Bober, Johan Auwerx, Kazuya Yamagata.
      Brown adipose tissue plays a central role in the regulation of the energy balance by expending energy to produce heat. NAD+-dependent deacylase sirtuins have widely been recognized as positive regulators of brown adipose tissue thermogenesis. However, here we reveal that SIRT7, one of seven mammalian sirtuins, suppresses energy expenditure and thermogenesis by regulating brown adipose tissue functions. Whole-body and brown adipose tissue-specific Sirt7 knockout mice have higher body temperature and energy expenditure. SIRT7 deficiency increases the protein level of UCP1, a key regulator of brown adipose tissue thermogenesis. Mechanistically, we found that SIRT7 deacetylates insulin-like growth factor 2 mRNA-binding protein 2, an RNA-binding protein that inhibits the translation of Ucp1 mRNA, thereby enhancing its inhibitory action on Ucp1. Furthermore, SIRT7 attenuates the expression of batokine genes, such as fibroblast growth factor 21. In conclusion, we propose that SIRT7 serves as an energy-saving factor by suppressing brown adipose tissue functions.
    DOI:  https://doi.org/10.1038/s41467-022-35219-z
  26. Cell. 2022 Dec 07. pii: S0092-8674(22)01460-X. [Epub ahead of print]
    Engineered cell entry links receptor biology with single-cell genomics.
    Bingfei Yu, Quanming Shi, Julia A Belk, Kathryn E Yost, Kevin R Parker, Rui Li, Betty B Liu, Huang Huang, Daniel Lingwood, William J Greenleaf, Mark M Davis, Ansuman T Satpathy, Howard Y Chang.
      Cells communicate with each other via receptor-ligand interactions. Here, we describe lentiviral-mediated cell entry by engineered receptor-ligand interaction (ENTER) to display ligand proteins, deliver payloads, and record receptor specificity. We optimize ENTER to decode interactions between T cell receptor (TCR)-MHC peptides, antibody-antigen, and other receptor-ligand pairs. A viral presentation strategy allows ENTER to capture interactions between B cell receptor and any antigen. We engineer ENTER to deliver genetic payloads to antigen-specific T or B cells to selectively modulate cellular behavior in mixed populations. Single-cell readout of ENTER by RNA sequencing (ENTER-seq) enables multiplexed enumeration of antigen specificities, TCR clonality, cell type, and states of individual T cells. ENTER-seq of CMV-seropositive patient blood samples reveals the viral epitopes that drive effector memory T cell differentiation and inter-clonal vs. intra-clonal phenotypic diversity targeting the same epitope. ENTER technology enables systematic discovery of receptor specificity, linkage to cell fates, and antigen-specific cargo delivery.
    Keywords:  B cell receptor; T cell receptor; antigen specificity; ligand-receptor pairs; single-cell multiomics; targeted cargo delivery; viral display; virus-like particle
    DOI:  https://doi.org/10.1016/j.cell.2022.11.016
  27. J Exp Med. 2023 Mar 06. pii: e20221090. [Epub ahead of print]220(3):
    cDC1-derived IL-27 regulates small intestinal CD4+ T cell homeostasis in mice.
    Fatemeh Ahmadi, Fredrik Junghus, Christian Ashworth, Amanda Lappalainen, Urs Mörbe, Knut Kotarsky, William W Agace.
      The small intestinal lamina propria contains large numbers of IFNγ-producing T helper (Th1) cells that play important roles in intestinal homeostasis and host defense, but the mechanisms underlying their development remain poorly understood. Here, we demonstrate that Th1 cells accumulate in the SI-LP after weaning and are maintained there long term. While both Th17 and Th1 cell accumulation in the SI-LP was microbiota dependent, Th1 cell accumulation uniquely required IL-27 and MHCII expression by cDC1. This reflected a requirement for IL-27 signaling in the priming of Th1 cells rather than for their maintenance once in the mucosa. cDC1-derived IL-27 was essential for maintaining the Th1-Th17 balance within the SI-LP, and in its absence, remaining Th1 cells expressed enhanced levels of Th17 signature genes. In conclusion, we identify cDC1-derived IL-27 as a key regulator of SI-LP Th1-Th17 cell homeostasis.
    DOI:  https://doi.org/10.1084/jem.20221090
  28. Science. 2022 Dec 16. 378(6625): 1227-1234
    Multidimensional control of therapeutic human cell function with synthetic gene circuits.
    Hui-Shan Li, Divya V Israni, Keith A Gagnon, Kok Ann Gan, Michael H Raymond, Jeffry D Sander, Kole T Roybal, J Keith Joung, Wilson W Wong, Ahmad S Khalil.
      Synthetic gene circuits that precisely control human cell function could expand the capabilities of gene- and cell-based therapies. However, platforms for developing circuits in primary human cells that drive robust functional changes in vivo and have compositions suitable for clinical use are lacking. Here, we developed synthetic zinc finger transcription regulators (synZiFTRs), which are compact and based largely on human-derived proteins. As a proof of principle, we engineered gene switches and circuits that allow precise, user-defined control over therapeutically relevant genes in primary T cells using orthogonal, US Food and Drug Administration-approved small-molecule inducers. Our circuits can instruct T cells to sequentially activate multiple cellular programs such as proliferation and antitumor activity to drive synergistic therapeutic responses. This platform should accelerate the development and clinical translation of synthetic gene circuits in diverse human cell types and contexts.
    DOI:  https://doi.org/10.1126/science.ade0156
  29. Nat Commun. 2022 Dec 12. 13(1): 7677
    PRDM1/BLIMP1 induces cancer immune evasion by modulating the USP22-SPI1-PD-L1 axis in hepatocellular carcinoma cells.
    Qing Li, Liren Zhang, Wenhua You, Jiali Xu, Jingjing Dai, Dongxu Hua, Ruizhi Zhang, Feifan Yao, Suiqing Zhou, Wei Huang, Yongjiu Dai, Yu Zhang, Tasiken Baheti, Xiaofeng Qian, Liyong Pu, Jing Xu, Yongxiang Xia, Chuanyong Zhang, Jinhai Tang, Xuehao Wang.
      Programmed death receptor-1 (PD-1) blockade have achieved some efficacy but only in a fraction of patients with hepatocellular carcinoma (HCC). Programmed cell death 1 ligand 1 (PD-L1) binds to its receptor PD1 on T cells to dampen antigen-tumor immune responses. However, the mechanisms underlying PD-L1 regulation are not fully elucidated. Herein, we identify that tumoral Prdm1 overexpression inhibits cell growth in immune-deficient mouse models. Further, tumoral Prdm1 overexpression upregulates PD-L1 levels, dampening anti-tumor immunity in vivo, and neutralizes the anti-tumor efficacy of Prdm1 overexpression in immune-competent mouse models. Mechanistically, PRDM1 enhances USP22 transcription, thus reducing SPI1 protein degradation through deubiquitination, which enhances PD-L1 transcription. Functionally, PD-1 mAb treatment reinforces the efficacy of Prdm1-overexpressing HCC immune-competent mouse models. Collectively, we demonstrate that the PRDM1-USP22-SPI1 axis regulates PD-L1 levels, resulting in infiltrated CD8+ T cell exhaustion. Furthermore, PRDM1 overexpression combined with PD-(L)1 mAb treatment provides a therapeutic strategy for HCC treatment.
    DOI:  https://doi.org/10.1038/s41467-022-35469-x
  30. Nat Commun. 2022 Dec 13. 13(1): 7709
    Deep brain stimulation creates informational lesion through membrane depolarization in mouse hippocampus.
    Eric Lowet, Krishnakanth Kondabolu, Samuel Zhou, Rebecca A Mount, Yangyang Wang, Cara R Ravasio, Xue Han.
      Deep brain stimulation (DBS) is a promising neuromodulation therapy, but the neurophysiological mechanisms of DBS remain unclear. In awake mice, we performed high-speed membrane voltage fluorescence imaging of individual hippocampal CA1 neurons during DBS delivered at 40 Hz or 140 Hz, free of electrical interference. DBS powerfully depolarized somatic membrane potentials without suppressing spike rate, especially at 140 Hz. Further, DBS paced membrane voltage and spike timing at the stimulation frequency and reduced timed spiking output in response to hippocampal network theta-rhythmic (3-12 Hz) activity patterns. To determine whether DBS directly impacts cellular processing of inputs, we optogenetically evoked theta-rhythmic membrane depolarization at the soma. We found that DBS-evoked membrane depolarization was correlated with DBS-mediated suppression of neuronal responses to optogenetic inputs. These results demonstrate that DBS produces powerful membrane depolarization that interferes with the ability of individual neurons to respond to inputs, creating an informational lesion.
    DOI:  https://doi.org/10.1038/s41467-022-35314-1
  31. Nat Commun. 2022 Dec 13. 13(1): 7704
    Activation of a transient progenitor state in the epicardium is required for zebrafish heart regeneration.
    Yu Xia, Sierra Duca, Björn Perder, Friederike Dündar, Paul Zumbo, Miaoyan Qiu, Jun Yao, Yingxi Cao, Michael R M Harrison, Lior Zangi, Doron Betel, Jingli Cao.
      The epicardium, a mesothelial cell tissue that encompasses vertebrate hearts, supports heart regeneration after injury through paracrine effects and as a source of multipotent progenitors. However, the progenitor state in the adult epicardium has yet to be defined. Through single-cell RNA-sequencing of isolated epicardial cells from uninjured and regenerating adult zebrafish hearts, we define the epithelial and mesenchymal subsets of the epicardium. We further identify a transiently activated epicardial progenitor cell (aEPC) subpopulation marked by ptx3a and col12a1b expression. Upon cardiac injury, aEPCs emerge from the epithelial epicardium, migrate to enclose the wound, undergo epithelial-mesenchymal transition (EMT), and differentiate into mural cells and pdgfra+hapln1a+ mesenchymal epicardial cells. These EMT and differentiation processes are regulated by the Tgfβ pathway. Conditional ablation of aEPCs blocks heart regeneration through reduced nrg1 expression and mesenchymal cell number. Our findings identify a transient progenitor population of the adult epicardium that is indispensable for heart regeneration and highlight it as a potential target for enhancing cardiac repair.
    DOI:  https://doi.org/10.1038/s41467-022-35433-9
  32. Cell Rep. 2022 Dec 13. pii: S2211-1247(22)01677-1. [Epub ahead of print]41(11): 111789
    The mitochondrial UPR regulator ATF5 promotes intestinal barrier function via control of the satiety response.
    Douja Chamseddine, Siraje A Mahmud, Aundrea K Westfall, Todd A Castoe, Rance E Berg, Mark W Pellegrino.
      Organisms use several strategies to mitigate mitochondrial stress, including the activation of the mitochondrial unfolded protein response (UPRmt). The UPRmt in Caenorhabditis elegans, regulated by the transcription factor ATFS-1, expands on this recovery program by inducing an antimicrobial response against pathogens that target mitochondrial function. Here, we show that the mammalian ortholog of ATFS-1, ATF5, protects the host during infection with enteric pathogens but, unexpectedly, by maintaining the integrity of the intestinal barrier. Intriguingly, ATF5 supports intestinal barrier function by promoting a satiety response that prevents obesity and associated hyperglycemia. This consequently averts dysregulated glucose metabolism that is detrimental to barrier function. Mechanistically, we show that intestinal ATF5 stimulates the satiety response by transcriptionally regulating the gastrointestinal peptide hormone cholecystokinin, which promotes the secretion of the hormone leptin. We propose that ATF5 protects the host from enteric pathogens by promoting intestinal barrier function through a satiety-response-mediated metabolic control mechanism.
    Keywords:  ATF5; CP: Metabolism; CP: Molecular biology; UPR(mt); cholecystokinin; colitis; epithelial barrier; host-pathogen interaction; hyperglycemia; leptin; mitochondria; satiety
    DOI:  https://doi.org/10.1016/j.celrep.2022.111789
  33. J Exp Med. 2023 Mar 06. pii: e20221316. [Epub ahead of print]220(3):
    Repurposing a tricyclic antidepressant in tumor and metabolism disease treatment through fatty acid uptake inhibition.
    Qiaoyun Chu, Jing An, Ping Liu, Yihan Song, Xuewei Zhai, Ronghui Yang, Jing Niu, Chuanzhen Yang, Binghui Li.
      Fatty acid uptake is essential for cell physiological function, but detailed mechanisms remain unclear. Here, we generated an acetyl-CoA carboxylases (ACC1/2) double-knockout cell line, which lacked fatty acid biosynthesis and survived on serum fatty acids and was used to screen for fatty acid uptake inhibitors. We identified a Food and Drug Administration-approved tricyclic antidepressant, nortriptyline, that potently blocked fatty acid uptake both in vitro and in vivo. We also characterized underlying mechanisms whereby nortriptyline provoked lysosomes to release protons and induce cell acidification to suppress macropinocytosis, which accounted for fatty acid endocytosis. Furthermore, nortriptyline alone or in combination with ND-646, a selective ACC1/2 inhibitor, significantly repressed tumor growth, lipogenesis, and hepatic steatosis in mice. Therefore, we show that cells actively take up fatty acids through macropinocytosis, and we provide a potential strategy suppressing tumor growth, lipogenesis, and hepatic steatosis through controlling the cellular level of fatty acids.
    DOI:  https://doi.org/10.1084/jem.20221316
  34. Sci Adv. 2022 Dec 14. 8(50): eadd0695
    TATTOO-seq delineates spatial and cell type-specific regulatory programs in the developing limb.
    Sébastien Bastide, Elad Chomsky, Baptiste Saudemont, Yann Loe-Mie, Sandrine Schmutz, Sophie Novault, Heather Marlow, Amos Tanay, François Spitz.
      The coordinated differentiation of progenitor cells into specialized cell types and their spatial organization into distinct domains is central to embryogenesis. Here, we developed and applied an unbiased spatially resolved single-cell transcriptomics method to identify the genetic programs underlying the emergence of specialized cell types during mouse limb development and their spatial integration. We identify multiple transcription factors whose expression patterns are predominantly associated with cell type specification or spatial position, suggesting two parallel yet highly interconnected regulatory systems. We demonstrate that the embryonic limb undergoes a complex multiscale reorganization upon perturbation of one of its spatial organizing centers, including the loss of specific cell populations, alterations of preexisting cell states' molecular identities, and changes in their relative spatial distribution. Our study shows how multidimensional single-cell, spatially resolved molecular atlases can allow the deconvolution of spatial identity and cell fate and reveal the interconnected genetic networks that regulate organogenesis and its reorganization upon genetic alterations.
    DOI:  https://doi.org/10.1126/sciadv.add0695
  35. Nat Commun. 2022 Dec 10. 13(1): 7652
    Causal inference in medical records and complementary systems pharmacology for metformin drug repurposing towards dementia.
    Marie-Laure Charpignon, Bella Vakulenko-Lagun, Bang Zheng, Colin Magdamo, Bowen Su, Kyle Evans, Steve Rodriguez, Artem Sokolov, Sarah Boswell, Yi-Han Sheu, Melek Somai, Lefkos Middleton, Bradley T Hyman, Rebecca A Betensky, Stan N Finkelstein, Roy E Welsch, Ioanna Tzoulaki, Deborah Blacker, Sudeshna Das, Mark W Albers.
      Metformin, a diabetes drug with anti-aging cellular responses, has complex actions that may alter dementia onset. Mixed results are emerging from prior observational studies. To address this complexity, we deploy a causal inference approach accounting for the competing risk of death in emulated clinical trials using two distinct electronic health record systems. In intention-to-treat analyses, metformin use associates with lower hazard of all-cause mortality and lower cause-specific hazard of dementia onset, after accounting for prolonged survival, relative to sulfonylureas. In parallel systems pharmacology studies, the expression of two AD-related proteins, APOE and SPP1, was suppressed by pharmacologic concentrations of metformin in differentiated human neural cells, relative to a sulfonylurea. Together, our findings suggest that metformin might reduce the risk of dementia in diabetes patients through mechanisms beyond glycemic control, and that SPP1 is a candidate biomarker for metformin's action in the brain.
    DOI:  https://doi.org/10.1038/s41467-022-35157-w
  36. Nat Commun. 2022 Dec 16. 13(1): 7782
    Hepatic neddylation deficiency triggers fatal liver injury via inducing NF-κB-inducing kinase in mice.
    Cheng Xu, Hongyi Zhou, Yulan Jin, Khushboo Sahay, Anna Robicsek, Yisong Liu, Kunzhe Dong, Jiliang Zhou, Amanda Barrett, Huabo Su, Weiqin Chen.
      The conjugation of neural precursor cell expressed, developmentally downregulated 8 (NEDD8) to target proteins, termed neddylation, participates in many cellular processes and is aberrant in various pathological diseases. Its relevance to liver function and failure remains poorly understood. Herein, we show dysregulated expression of NAE1, a regulatory subunit of the only NEDD8 E1 enzyme, in human acute liver failure. Embryonic- and adult-onset deletion of NAE1 in hepatocytes causes hepatocyte death, inflammation, and fibrosis, culminating in fatal liver injury in mice. Hepatic neddylation deficiency triggers oxidative stress, mitochondrial dysfunction, and hepatocyte reprogramming, potentiating liver injury. Importantly, NF-κB-inducing kinase (NIK), a serine/Thr kinase, is a neddylation substrate. Neddylation of NIK promotes its ubiquitination and degradation. Inhibition of neddylation conversely causes aberrant NIK activation, accentuating hepatocyte damage and inflammation. Administration of N-acetylcysteine, a glutathione surrogate and antioxidant, mitigates liver failure caused by hepatic NAE1 deletion in adult male mice. Therefore, hepatic neddylation is important in maintaining postnatal and adult liver homeostasis, and the identified neddylation targets/pathways provide insights into therapeutically intervening acute liver failure.
    DOI:  https://doi.org/10.1038/s41467-022-35525-6
  37. J Immunol. 2022 Dec 14. pii: ji2200444. [Epub ahead of print]
    Lipopolysaccharide Primes Human Macrophages for Noncanonical Inflammasome-Induced Extracellular Vesicle Secretion.
    Wojciech Cypryk, Liliana Czernek, Katarzyna Horodecka, Jędrzej Chrzanowski, Marcin Stańczak, Katariina Nurmi, Marcelina Bilicka, Mariusz Gadzinowski, Aurelia Walczak-Drzewiecka, Maria Stensland, Kari Eklund, Wojciech Fendler, Tuula A Nyman, Sampsa Matikainen.
      Human macrophages secrete extracellular vesicles (EVs) loaded with numerous immunoregulatory proteins. Vesicle-mediated protein secretion in macrophages is regulated by poorly characterized mechanisms; however, it is now known that inflammatory conditions significantly alter both the quantities and protein composition of secreted vesicles. In this study, we employed high-throughput quantitative proteomics to characterize the modulation of EV-mediated protein secretion during noncanonical caspase-4/5 inflammasome activation via LPS transfection. We show that human macrophages activate robust caspase-4-dependent EV secretion upon transfection of LPS, and this process is also partially dependent on NLRP3 and caspase-5. A similar effect occurs with delivery of the LPS with Escherichia coli-derived outer membrane vesicles. Moreover, sensitization of the macrophages through TLR4 by LPS priming prior to LPS transfection dramatically augments the EV-mediated protein secretion. Our data demonstrate that this process differs significantly from canonical inflammasome activator ATP-induced vesiculation, and it is dependent on the autocrine IFN signal associated with TLR4 activation. LPS priming preceding the noncanonical inflammasome activation significantly enhances vesicle-mediated secretion of inflammasome components caspase-1, ASC, and lytic cell death effectors GSDMD, MLKL, and NINJ1, suggesting that inflammatory EV transfer may exert paracrine effects in recipient cells. Moreover, using bioinformatics methods, we identify 15-deoxy-Δ12,14-PGJ2 and parthenolide as inhibitors of caspase-4-mediated inflammation and vesicle secretion, indicating new therapeutic potential of these anti-inflammatory drugs.
    DOI:  https://doi.org/10.4049/jimmunol.2200444
  38. Sci Transl Med. 2022 Dec 14. 14(675): eabl3651
    A multiple sclerosis-protective coding variant reveals an essential role for HDAC7 in regulatory T cells.
    Pierre-Paul Axisa, Tomomi M Yoshida, Liliana E Lucca, Herbert G Kasler, Matthew R Lincoln, Giang H Pham, Dante Del Priore, Jean-Marie Carpier, Carrie L Lucas, Eric Verdin, Tomokazu S Sumida, David A Hafler.
      Genome-wide association studies identifying hundreds of susceptibility loci for autoimmune diseases indicate that genes active in immune cells predominantly mediate risk. However, identification and functional characterization of causal variants remain challenging. Here, we focused on the immunomodulatory role of a protective variant of histone deacetylase 7 (HDAC7). This variant (rs148755202, HDAC7.p.R166H) was identified in a study of low-frequency coding variation in multiple sclerosis (MS). Through transcriptomic analyses, we demonstrate that wild-type HDAC7 regulates genes essential for the function of Foxp3+ regulatory T cells (Tregs), an immunosuppressive subset of CD4 T cells that is generally dysfunctional in patients with MS. Moreover, Treg-specific conditional hemizygous deletion of HDAC7 increased the severity of experimental autoimmune encephalitis (EAE), a mouse model of neuroinflammation. In contrast, Tregs transduced with the protective HDAC7 R166H variant exhibited higher suppressive capacity in an in vitro functional assay, mirroring phenotypes previously observed in patient samples. In vivo modeling of the human HDAC7 R166H variant by generation of a knock-in mouse model bearing an orthologous R150H substitution demonstrated decreased EAE severity linked to transcriptomic alterations of brain-infiltrating Tregs, as assessed by single-cell RNA sequencing. Our data suggest that dysregulation of epigenetic modifiers, a distinct molecular class associated with disease risk, may influence disease onset. Last, our approach provides a template for the translation of genetic susceptibility loci to detailed functional characterization, using in vitro and in vivo modeling.
    DOI:  https://doi.org/10.1126/scitranslmed.abl3651
  39. Front Immunol. 2022 ;13 1038134
    Caspase-8 activation in neutrophils facilitates autoimmune kidney vasculitis through regulating CD4+ effector memory T cells.
    Jian Hu, Zhen Huang, Min Yu, Pei Zhang, Zhengkun Xia, Chunlin Gao.
      Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAVs) are closely associated with neutrophil recruitment and activation, but the impact of the neutrophil apoptosis process in autoimmune disease has been rarely explained. Here, by integrating and analyzing single-cell transcriptome datasets, we found that the caspase-8-associated pathway in neutrophils was highly activated in the kidney rather than in the blood. To verify the function of caspase-8 in neutrophils on AAVs progression, we constructed neutrophil-specific caspase-8 knockout mice combined with an AAVs model induced by human ANCA from AAVs patients, a rapid and powerful model developed in this study. Our results show that caspase-8 activation of neutrophils up-regulates the expression of several inflammatory and immunoregulatory factors, especially IL23A, regulating the activation and differentiation of tissue-resident CD4+ effector memory T cells. This study reveals that the activation of caspase-8 in neutrophils can worsen glomerulonephritis of AAVs by regulating inflammation and immunity.
    Keywords:  anti-neutrophil cytoplasmic antibody (ANCA); caspase-8; immunity; kidney vasculitis; neutrophil; single-cell transcriptome
    DOI:  https://doi.org/10.3389/fimmu.2022.1038134
  40. J Clin Invest. 2022 Dec 13. pii: e157907. [Epub ahead of print]
    TIGIT inhibition and lenalidomide synergistically promote anti-myeloma immune responses after stem cell transplantation in mice.
    Simone A Minnie, Olivia G Waltner, Kathleen S Ensbey, Stuart D Olver, Alika D Collinge, David P Sester, Christine R Schmidt, Samuel Rw Legg, Shuichiro Takahashi, Nicole S Nemychenkov, Tomoko Sekiguchi, Gregory Driessens, Ping Zhang, Motoko Koyama, Andrew Spencer, Leona A Holmberg, Scott N Furlan, Antiopi Varelias, Geoffrey R Hill.
      Autologous stem cell transplantation (ASCT), with subsequent lenalidomide maintenance is standard consolidation therapy for multiple myeloma and a subset of patients achieve durable progression-free survival that is suggestive of long-term immune control. Nonetheless, most patients ultimately relapse, suggesting immune escape. TIGIT appears a potent inhibitor of myeloma-specific immunity and represents a promising checkpoint target. Here we demonstrate high expression of TIGIT on activated CD8 T cells in mobilized peripheral blood stem cell grafts from patients with myeloma. To guide clinical application of TIGIT inhibition, we evaluated identical TIGIT Abs that do or do not engage FcγR and demonstrated that anti-TIGIT activity is dependent on FcγR binding. We subsequently used CRBN mice to investigate the efficacy of anti-TIGIT in combination with lenalidomide maintenance after transplantation. Notably, the combination of anti-TIGIT with lenalidomide provided synergistic, CD8 T cell-dependent, anti-myeloma efficacy. Analysis of bone marrow (BM) CD8 T cells demonstrated that combination therapy suppressed T cell exhaustion, enhanced effector function, and expanded central memory subsets. Importantly, these immune phenotypes were specific to the BM tumor microenvironment. Collectively, these data provide a logical rationale for combining TIGIT inhibition with immunomodulatory drugs to prevent myeloma progression after stem cell transplantation.
    Keywords:  Adaptive immunity; Bone marrow transplantation; Cancer immunotherapy; Immunology; Oncology
    DOI:  https://doi.org/10.1172/JCI157907
  41. Nat Commun. 2022 Dec 12. 13(1): 7671
    An atlas of late prenatal human neurodevelopment resolved by single-nucleus transcriptomics.
    Susana I Ramos, Zarmeen M Mussa, Elisa N Falk, Balagopal Pai, Bruno Giotti, Kimaada Allette, Peiwen Cai, Fumiko Dekio, Robert Sebra, Kristin G Beaumont, Alexander M Tsankov, Nadejda M Tsankova.
      Late prenatal development of the human neocortex encompasses a critical period of gliogenesis and cortical expansion. However, systematic single-cell analyses to resolve cellular diversity and gliogenic lineages of the third trimester are lacking. Here, we present a comprehensive single-nucleus RNA sequencing atlas of over 200,000 nuclei derived from the proliferative germinal matrix and laminating cortical plate of 15 prenatal, non-pathological postmortem samples from 17 to 41 gestational weeks, and 3 adult controls. This dataset captures prenatal gliogenesis with high temporal resolution and is provided as a resource for further interrogation. Our computational analysis resolves greater complexity of glial progenitors, including transient glial intermediate progenitor cell (gIPC) and nascent astrocyte populations in the third trimester of human gestation. We use lineage trajectory and RNA velocity inference to further characterize specific gIPC subpopulations preceding both oligodendrocyte (gIPC-O) and astrocyte (gIPC-A) lineage differentiation. We infer unique transcriptional drivers and biological pathways associated with each developmental state, validate gIPC-A and gIPC-O presence within the human germinal matrix and cortical plate in situ, and demonstrate gIPC states being recapitulated across adult and pediatric glioblastoma tumors.
    DOI:  https://doi.org/10.1038/s41467-022-34975-2
  42. Science. 2022 Dec 16. 378(6625): eaba1624
    Synthetic cytokine circuits that drive T cells into immune-excluded tumors.
    Greg M Allen, Nicholas W Frankel, Nishith R Reddy, Hersh K Bhargava, Maia A Yoshida, Sierra R Stark, Megan Purl, Jungmin Lee, Jacqueline L Yee, Wei Yu, Aileen W Li, K Christopher Garcia, Hana El-Samad, Kole T Roybal, Matthew H Spitzer, Wendell A Lim.
      Chimeric antigen receptor (CAR) T cells are ineffective against solid tumors with immunosuppressive microenvironments. To overcome suppression, we engineered circuits in which tumor-specific synNotch receptors locally induce production of the cytokine IL-2. These circuits potently enhance CAR T cell infiltration and clearance of immune-excluded tumors, without systemic toxicity. The most effective IL-2 induction circuit acts in an autocrine and T cell receptor (TCR)- or CAR-independent manner, bypassing suppression mechanisms including consumption of IL-2 or inhibition of TCR signaling. These engineered cells establish a foothold in the target tumors, with synthetic Notch-induced IL-2 production enabling initiation of CAR-mediated T cell expansion and cell killing. Thus, it is possible to reconstitute synthetic T cell circuits that activate the outputs ultimately required for an antitumor response, but in a manner that evades key points of tumor suppression.
    DOI:  https://doi.org/10.1126/science.aba1624
  43. JAMA. 2022 12 13. 328(22): 2201
    "Off-the-Shelf" CAR T-Cell Therapy Tested in Pediatric B-Cell Leukemia.
    Howard Larkin.
      
    DOI:  https://doi.org/10.1001/jama.2022.20033
  44. Nature. 2022 Dec 15.
    RSV wave hammers hospitals - but vaccines and treatments are coming.
    Rachel Fairbank.
      
    Keywords:  Diseases; Public health; Vaccines; Virology
    DOI:  https://doi.org/10.1038/d41586-022-04434-5
  45. Nat Commun. 2022 Dec 12. 13(1): 7690
    Brain metastatic outgrowth and osimertinib resistance are potentiated by RhoA in EGFR-mutant lung cancer.
    Sally J Adua, Anna Arnal-Estapé, Minghui Zhao, Bowen Qi, Zongzhi Z Liu, Carolyn Kravitz, Heather Hulme, Nicole Strittmatter, Francesc López-Giráldez, Sampada Chande, Alexandra E Albert, Mary-Ann Melnick, Bomiao Hu, Katerina Politi, Veronica Chiang, Nicola Colclough, Richard J A Goodwin, Darren Cross, Paul Smith, Don X Nguyen.
      The brain is a major sanctuary site for metastatic cancer cells that evade systemic therapies. Through pre-clinical pharmacological, biological, and molecular studies, we characterize the functional link between drug resistance and central nervous system (CNS) relapse in Epidermal Growth Factor Receptor- (EGFR-) mutant non-small cell lung cancer, which can progress in the brain when treated with the CNS-penetrant EGFR inhibitor osimertinib. Despite widespread osimertinib distribution in vivo, the brain microvascular tumor microenvironment (TME) is associated with the persistence of malignant cell sub-populations, which are poised to proliferate in the brain as osimertinib-resistant lesions over time. Cellular and molecular features of this poised state are regulated through a Ras homolog family member A (RhoA) and Serum Responsive Factor (SRF) gene expression program. RhoA potentiates the outgrowth of disseminated tumor cells on osimertinib treatment, preferentially in response to extracellular laminin and in the brain. Thus, we identify pre-existing and adaptive features of metastatic and drug-resistant cancer cells, which are enhanced by RhoA/SRF signaling and the brain TME during the evolution of osimertinib-resistant disease.
    DOI:  https://doi.org/10.1038/s41467-022-34889-z
  46. JCI Insight. 2022 11 22. pii: e159136. [Epub ahead of print]7(22):
    Autophagy inducer rapamycin treatment reduces IFN-I-mediated Inflammation and improves anti-HIV-1 T cell response in vivo.
    Wenli Mu, Valerie Rezek, Heather Martin, Mayra A Carrillo, Shallu Tomer, Philip Hamid, Miguel A Lizarraga, Tristan D Tibbe, Otto O Yang, Beth D Jamieson, Scott G Kitchen, Anjie Zhen.
      A hallmark of HIV-1 infection is chronic inflammation, even in patients treated with antiretroviral therapy (ART). Chronic inflammation drives HIV-1 pathogenesis, leading to loss of CD4+ T cells and exhaustion of antiviral immunity. Therefore, strategies to safely reduce systematic inflammation are needed to halt disease progression and restore defective immune responses. Autophagy is a cellular mechanism for disposal of damaged organelles and elimination of intracellular pathogens. Autophagy is pivotal for energy homeostasis and plays critical roles in regulating immunity. However, how it regulates inflammation and antiviral T cell responses during HIV infection is unclear. Here, we demonstrate that autophagy is directly linked to IFN-I signaling, which is a key driver of immune activation and T cell exhaustion during chronic HIV infection. Impairment of autophagy leads to spontaneous IFN-I signaling, and autophagy induction reduces IFN-I signaling in monocytic cells. Importantly, in HIV-1-infected humanized mice, autophagy inducer rapamycin treatment significantly reduced persistent IFN-I-mediated inflammation and improved antiviral T cell responses. Cotreatment of rapamycin with ART led to significantly reduced viral rebound after ART withdrawal. Taken together, our data suggest that therapeutically targeting autophagy is a promising approach to treat persistent inflammation and improve immune control of HIV replication.
    Keywords:  AIDS/HIV; Cellular immune response; Inflammation; Innate immunity
    DOI:  https://doi.org/10.1172/jci.insight.159136
  47. J Clin Invest. 2022 Dec 13. pii: e164508. [Epub ahead of print]
    Glucose- and glutamine-dependent bioenergetics sensitize bone mechanoresponse after unloading by modulating osteocyte calcium dynamics.
    Xiyu Liu, Zedong Yan, Jing Cai, Dan Wang, Yongqing Yang, Yuanjun Ding, Xi Shao, Xiaoxia Hao, Erping Luo, X Edward Guo, Peng Luo, Liangliang Shen, Da Jing.
      Disuse osteoporosis is a metabolic bone disease resulted from skeletal unloading (e.g., during extended bed rest, limb immobilization, and spaceflight), and the slow and insufficient bone recovery during re-ambulation remains an unresolved medical challenge. Here, we demonstrated that loading-induced increase in bone architecture/strength was suppressed in skeletons previously exposed to unloading. This reduction in bone mechanosensitivity was directly associated with attenuated osteocytic Ca2+ oscillatory dynamics. The unloading-induced compromised osteocytic Ca2+ response to reloading resulted from the HIF-1α/PDK1 axis-mediated increase in glycolysis, and a subsequent reduction in ATP synthesis. HIF-1α also transcriptionally induced substantial glutaminase 2 expression and thereby glutamine addiction in osteocytes. Inhibition of glycolysis by blocking PDK1 or glutamine supplementation restored the mechanosensitivity in those skeletons with previous unloading by fueling the tricarboxylic acid cycle and rescuing subsequent Ca2+ oscillations in osteocytes. Thus, we provide a mechanistic insight into disuse-induced deterioration of bone mechanosensitivity and a promising therapeutic approach to accelerate bone recovery after long-duration disuse.
    Keywords:  Bioenergetics; Bone Biology; Bone disease; Calcium signaling
    DOI:  https://doi.org/10.1172/JCI164508
  48. JCI Insight. 2022 11 22. pii: e138539. [Epub ahead of print]7(22):
    Activated cholesterol metabolism is integral for innate macrophage responses by amplifying Myd88 signaling.
    Sumio Hayakawa, Atsushi Tamura, Nikita Nikiforov, Hiroyuki Koike, Fujimi Kudo, Yinglan Cheng, Takuro Miyazaki, Marina Kubekina, Tatiana V Kirichenko, Alexander N Orekhov, Nobuhiko Yui, Ichiro Manabe, Yumiko Oishi.
      Recent studies have shown that cellular metabolism is tightly linked to the regulation of immune cells. Here, we show that activation of cholesterol metabolism, involving cholesterol uptake, synthesis, and autophagy/lipophagy, is integral to innate immune responses in macrophages. In particular, cholesterol accumulation within endosomes and lysosomes is a hallmark of the cellular cholesterol dynamics elicited by Toll-like receptor 4 activation and is required for amplification of myeloid differentiation primary response 88 (Myd88) signaling. Mechanistically, Myd88 binds cholesterol via its CLR recognition/interaction amino acid consensus domain, which promotes the protein's self-oligomerization. Moreover, a novel supramolecular compound, polyrotaxane (PRX), inhibited Myd88‑dependent inflammatory macrophage activation by decreasing endolysosomal cholesterol via promotion of cholesterol trafficking and efflux. PRX activated liver X receptor, which led to upregulation of ATP binding cassette transporter A1, thereby promoting cholesterol efflux. PRX also inhibited atherogenesis in Ldlr-/- mice. In humans, cholesterol levels in circulating monocytes correlated positively with the severity of atherosclerosis. These findings demonstrate that dynamic changes in cholesterol metabolism are mechanistically linked to Myd88‑dependent inflammatory programs in macrophages and support the notion that cellular cholesterol metabolism is integral to innate activation of macrophages and is a potential therapeutic and diagnostic target for inflammatory diseases.
    Keywords:  Inflammation; Innate immunity; Vascular Biology
    DOI:  https://doi.org/10.1172/jci.insight.138539
  49. Cell Rep. 2022 Dec 13. pii: S2211-1247(22)01679-5. [Epub ahead of print]41(11): 111791
    Species-specific rewiring of definitive endoderm developmental gene activation via endogenous retroviruses through TET1-mediated demethylation.
    Fang Wu, Zhongqi Liufu, Yujian Liu, Lin Guo, Jian Wu, Shangtao Cao, Yue Qin, Ning Guo, Yunyun Fu, He Liu, Qiuhong Li, Xiaodong Shu, Duanqing Pei, Andrew P Hutchins, Jiekai Chen, Jiangping He.
      Transposable elements (TEs) are the major sources of lineage-specific genomic innovation and comprise nearly half of the human genome, but most of their functions remain unclear. Here, we identify that a series of endogenous retroviruses (ERVs), a TE subclass, regulate the transcriptome at the definitive endoderm stage with in vitro differentiation model from human embryonic stem cell. Notably, these ERVs perform as enhancers containing binding sites for critical transcription factors for endoderm lineage specification. Genome-wide methylation analysis shows most of these ERVs are derepressed by TET1-mediated DNA demethylation. LTR6B, a representative definitive endoderm activating ERV, contains binding sites for FOXA2 and GATA4 and governs the primate-specific expression of its neighboring developmental genes such as ERBB4 in definitive endoderm. Together, our study proposes evidence that recently evolved ERVs represent potent de novo developmental regulatory elements, which, in turn, fine-tune species-specific transcriptomes during endoderm and embryonic development.
    Keywords:  CP: Developmental biology; CP: Molecular biology; DNA methylation; TET1; endogenous retroviruses; gene regulation; human development; transcriptional networks; transposable elements
    DOI:  https://doi.org/10.1016/j.celrep.2022.111791
  50. Cell Rep. 2022 Dec 13. pii: S2211-1247(22)01685-0. [Epub ahead of print]41(11): 111797
    Recruited monocytes/macrophages drive pulmonary neutrophilic inflammation and irreversible lung tissue remodeling in cystic fibrosis.
    Hasan H Öz, Ee-Chun Cheng, Caterina Di Pietro, Toma Tebaldi, Giulia Biancon, Caroline Zeiss, Ping-Xia Zhang, Pamela H Huang, Sofia S Esquibies, Clemente J Britto, Jonas C Schupp, Thomas S Murray, Stephanie Halene, Diane S Krause, Marie E Egan, Emanuela M Bruscia.
      Persistent neutrophil-dominated lung inflammation contributes to lung damage in cystic fibrosis (CF). However, the mechanisms that drive persistent lung neutrophilia and tissue deterioration in CF are not well characterized. Starting from the observation that, in patients with CF, c-c motif chemokine receptor 2 (CCR2)+ monocytes/macrophages are abundant in the lungs, we investigate the interplay between monocytes/macrophages and neutrophils in perpetuating lung tissue damage in CF. Here we show that CCR2+ monocytes in murine CF lungs drive pathogenic transforming growth factor β (TGF-β) signaling and sustain a pro-inflammatory environment by facilitating neutrophil recruitment. Targeting CCR2 to lower the numbers of monocytes in CF lungs ameliorates neutrophil inflammation and pathogenic TGF-β signaling and prevents lung tissue damage. This study identifies CCR2+ monocytes as a neglected contributor to the pathogenesis of CF lung disease and as a therapeutic target for patients with CF, for whom lung hyperinflammation and tissue damage remain an issue despite recent advances in CF transmembrane conductance regulator (CFTR)-specific therapeutic agents.
    Keywords:  CP: Immunology; c-c motif chemokine receptor 2; chronic lung inflammation; cystic fibrosis; lipopolysaccharide; lung remodeling; macrophages; monocytes; neutrophils; recruitment; transforming growth factor β
    DOI:  https://doi.org/10.1016/j.celrep.2022.111797
  51. Nat Commun. 2022 Dec 13. 13(1): 7729
    Spatial transcriptomics landscape of lesions from non-communicable inflammatory skin diseases.
    A Schäbitz, C Hillig, M Mubarak, M Jargosch, A Farnoud, E Scala, N Kurzen, A C Pilz, N Bhalla, J Thomas, M Stahle, T Biedermann, C B Schmidt-Weber, F Theis, N Garzorz-Stark, K Eyerich, M P Menden, S Eyerich.
      Abundant heterogeneous immune cells infiltrate lesions in chronic inflammatory diseases and characterization of these cells is needed to distinguish disease-promoting from bystander immune cells. Here, we investigate the landscape of non-communicable inflammatory skin diseases (ncISD) by spatial transcriptomics resulting in a large repository of 62,000 spatially defined human cutaneous transcriptomes from 31 patients. Despite the expected immune cell infiltration, we observe rather low numbers of pathogenic disease promoting cytokine transcripts (IFNG, IL13 and IL17A), i.e. >125 times less compared to the mean expression of all other genes over lesional skin sections. Nevertheless, cytokine expression is limited to lesional skin and presented in a disease-specific pattern. Leveraging a density-based spatial clustering method, we identify specific responder gene signatures in direct proximity of cytokines, and confirm that detected cytokine transcripts initiate amplification cascades of up to thousands of specific responder transcripts forming localized epidermal clusters. Thus, within the abundant and heterogeneous infiltrates of ncISD, only a low number of cytokine transcripts and their translated proteins promote disease by initiating an inflammatory amplification cascade in their local microenvironment.
    DOI:  https://doi.org/10.1038/s41467-022-35319-w
  52. Nat Commun. 2022 Dec 12. 13(1): 7689
    Regulation of bone homeostasis by MERTK and TYRO3.
    Janik Engelmann, Jennifer Zarrer, Victoria Gensch, Kristoffer Riecken, Nikolaus Berenbrok, The Vinh Luu, Antonia Beitzen-Heineke, Maria Elena Vargas-Delgado, Klaus Pantel, Carsten Bokemeyer, Somasekhar Bhamidipati, Ihab S Darwish, Esteban Masuda, Tal Burstyn-Cohen, Emily J Alberto, Sourav Ghosh, Carla Rothlin, Eric Hesse, Hanna Taipaleenmäki, Isabel Ben-Batalla, Sonja Loges.
      The fine equilibrium of bone homeostasis is maintained by bone-forming osteoblasts and bone-resorbing osteoclasts. Here, we show that TAM receptors MERTK and TYRO3 exert reciprocal effects in osteoblast biology: Osteoblast-targeted deletion of MERTK promotes increased bone mass in healthy mice and mice with cancer-induced bone loss, whereas knockout of TYRO3 in osteoblasts shows the opposite phenotype. Functionally, the interaction of MERTK with its ligand PROS1 negatively regulates osteoblast differentiation via inducing the VAV2-RHOA-ROCK axis leading to increased cell contractility and motility while TYRO3 antagonizes this effect. Consequently, pharmacologic MERTK blockade by the small molecule inhibitor R992 increases osteoblast numbers and bone formation in mice. Furthermore, R992 counteracts cancer-induced bone loss, reduces bone metastasis and prolongs survival in preclinical models of multiple myeloma, breast- and lung cancer. In summary, MERTK and TYRO3 represent potent regulators of bone homeostasis with cell-type specific functions and MERTK blockade represents an osteoanabolic therapy with implications in cancer and beyond.
    DOI:  https://doi.org/10.1038/s41467-022-33938-x
  53. J Clin Invest. 2022 Dec 15. pii: e159672. [Epub ahead of print]132(24):
    Delivery of costimulatory blockade to lymph nodes promotes transplant acceptance in mice.
    Jing Zhao, Sungwook Jung, Xiaofei Li, Lushen Li, Vivek Kasinath, Hengcheng Zhang, Said N Movahedi, Ahmad Mardini, Gianmarco Sabiu, Yoonha Hwang, Vikas Saxena, Yang Song, Bing Ma, Sophie E Acton, Pilhan Kim, Joren C Madsen, Peter T Sage, Stefan G Tullius, George C Tsokos, Jonathan S Bromberg, Reza Abdi.
      The lymph node (LN) is the primary site of alloimmunity activation and regulation during transplantation. Here, we investigated how fibroblastic reticular cells (FRCs) facilitate the tolerance induced by anti-CD40L in a murine model of heart transplantation. We found that both the absence of LNs and FRC depletion abrogated the effect of anti-CD40L in prolonging murine heart allograft survival. Depletion of FRCs impaired homing of T cells across the high endothelial venules (HEVs) and promoted formation of alloreactive T cells in the LNs in heart-transplanted mice treated with anti-CD40L. Single-cell RNA sequencing of the LNs showed that anti-CD40L promotes a Madcam1+ FRC subset. FRCs also promoted the formation of regulatory T cells (Tregs) in vitro. Nanoparticles (NPs) containing anti-CD40L were selectively delivered to the LNs by coating them with MECA-79, which binds to peripheral node addressin (PNAd) glycoproteins expressed exclusively by HEVs. Treatment with these MECA-79-anti-CD40L-NPs markedly delayed the onset of heart allograft rejection and increased the presence of Tregs. Finally, combined MECA-79-anti-CD40L-NPs and rapamycin treatment resulted in markedly longer allograft survival than soluble anti-CD40L and rapamycin. These data demonstrate that FRCs are critical to facilitating costimulatory blockade. LN-targeted nanodelivery of anti-CD40L could effectively promote heart allograft acceptance.
    Keywords:  Organ transplantation; Transplantation
    DOI:  https://doi.org/10.1172/JCI159672
  54. Nat Commun. 2022 Dec 10. 13(1): 7644
    Structure of nucleosome-bound human PBAF complex.
    Li Wang, Jiali Yu, Zishuo Yu, Qianmin Wang, Wanjun Li, Yulei Ren, Zhenguo Chen, Shuang He, Yanhui Xu.
      BAF and PBAF are mammalian SWI/SNF family chromatin remodeling complexes that possess multiple histone/DNA-binding subunits and create nucleosome-depleted/free regions for transcription activation. Despite previous structural studies and recent advance of SWI/SNF family complexes, it remains incompletely understood how PBAF-nucleosome complex is organized. Here we determined structure of 13-subunit human PBAF in complex with acetylated nucleosome in ADP-BeF3-bound state. Four PBAF-specific subunits work together with nine BAF/PBAF-shared subunits to generate PBAF-specific modular organization, distinct from that of BAF at various regions. PBAF-nucleosome structure reveals six histone-binding domains and four DNA-binding domains/modules, the majority of which directly bind histone/DNA. This multivalent nucleosome-binding pattern, not observed in previous studies, suggests that PBAF may integrate comprehensive chromatin information to target genomic loci for function. Our study reveals molecular organization of subunits and histone/DNA-binding domains/modules in PBAF-nucleosome complex and provides structural insights into PBAF-mediated nucleosome association complimentary to the recently reported PBAF-nucleosome structure.
    DOI:  https://doi.org/10.1038/s41467-022-34859-5
  55. Sci Adv. 2022 Dec 14. 8(50): eade0764
    Mechanistic insight into female predominance in Alzheimer's disease based on aberrant protein S-nitrosylation of C3.
    Hongmei Yang, Chang-Ki Oh, Haitham Amal, John S Wishnok, Sarah Lewis, Emily Schahrer, Dorit Trudler, Tomohiro Nakamura, Steven R Tannenbaum, Stuart A Lipton.
      Protein S-nitros(yl)ation (SNO) is a posttranslational modification involved in diverse processes in health and disease and can contribute to synaptic damage in Alzheimer's disease (AD). To identify SNO proteins in AD brains, we used triaryl phosphine (SNOTRAP) combined with mass spectrometry (MS). We detected 1449 SNO proteins with 2809 SNO sites, representing a wide range of S-nitrosylated proteins in 40 postmortem AD and non-AD human brains from patients of both sexes. Integrative protein ranking revealed the top 10 increased SNO proteins, including complement component 3 (C3), p62 (SQSTM1), and phospholipase D3. Increased levels of S-nitrosylated C3 were present in female over male AD brains. Mechanistically, we show that formation of SNO-C3 is dependent on falling β-estradiol levels, leading to increased synaptic phagocytosis and thus synapse loss and consequent cognitive decline. Collectively, we demonstrate robust alterations in the S-nitrosoproteome that contribute to AD pathogenesis in a sex-dependent manner.
    DOI:  https://doi.org/10.1126/sciadv.ade0764
  56. Sci Rep. 2022 Dec 10. 12(1): 21401
    Stage-specific and cell type-specific requirements of ikzf1 during haematopoietic differentiation in zebrafish.
    Isabell Hess, Sagar, Connor O Meara, Dominic Grün, Michael Schorpp, Thomas Boehm.
      The zinc finger transcription factor Ikaros1 (Ikzf1) is required for lymphoid development in mammals. Four zinc fingers constitute its DNA binding domain and two zinc fingers are present in the C-terminal protein interaction module. We describe the phenotypes of zebrafish homozygous for two distinct mutant ikzf1 alleles. The IT325 variant lacks the C-terminal two zinc fingers, whereas the fr105 variant retains only the first zinc finger of the DNA binding domain. An intact ikzf1 gene is required for larval T cell development, whereas low levels of adult lymphoid development recover in the mutants. By contrast, the mutants exhibit a signature of increased myelopoiesis at larval and adult stages. Both mutations stimulate erythroid differentiation in larvae, indicating that the C-terminal zinc fingers negatively regulate the extent of red blood cell production. An unexpected differential effect of the two mutants on adult erythropoiesis suggests a direct requirement of an intact DNA binding domain for entry of progenitors into the red blood cell lineage. Collectively, our results reinforce the biological differences between larval and adult haematopoiesis, indicate a stage-specific function of ikzf1 in regulating the hierarchical bifurcations of differentiation, and assign distinct functions to the DNA binding domain and the C-terminal zinc fingers.
    DOI:  https://doi.org/10.1038/s41598-022-25978-6
  57. Mol Cell. 2022 Dec 06. pii: S1097-2765(22)01131-5. [Epub ahead of print]
    A rapid RIG-I signaling relay mediates efficient antiviral response.
    Daniel T Thoresen, Drew Galls, Benjamin Götte, Wenshuai Wang, Anna M Pyle.
      RIG-I is essential for host defense against viral pathogens, as it triggers the release of type I interferons upon encounter with viral RNA molecules. In this study, we show that RIG-I is rapidly and efficiently activated by small quantities of incoming viral RNA and that it relies exclusively on the constitutively expressed resident pool of RIG-I receptors for a strong antiviral response. Live-cell imaging of RIG-I following stimulation with viral or synthetic dsRNA reveals that RIG-I signaling occurs without mass aggregation at the mitochondrial membrane. By contrast, interferon-induced RIG-I protein becomes embedded in cytosolic aggregates that are functionally unrelated to signaling. These findings suggest that endogenous RIG-I efficiently recognizes viral RNA and rapidly relays an antiviral signal to MAVS via a transient signaling complex and that cellular aggregates of RIG-I have a function that is distinct from signaling.
    Keywords:  RIG-I; antiviral response; innate immunity; type I interferon response
    DOI:  https://doi.org/10.1016/j.molcel.2022.11.018
  58. Nature. 2022 Dec 14.
    Ovarian cancer mutational processes drive site-specific immune evasion.
    Ignacio Vázquez-García, Florian Uhlitz, Nicholas Ceglia, Jamie L P Lim, Michelle Wu, Neeman Mohibullah, Juliana Niyazov, Arvin Eric B Ruiz, Kevin M Boehm, Viktoria Bojilova, Christopher J Fong, Tyler Funnell, Diljot Grewal, Eliyahu Havasov, Samantha Leung, Arfath Pasha, Druv M Patel, Maryam Pourmaleki, Nicole Rusk, Hongyu Shi, Rami Vanguri, Marc J Williams, Allen W Zhang, Vance Broach, Dennis S Chi, Arnaud Da Cruz Paula, Ginger J Gardner, Sarah H Kim, Matthew Lennon, Kara Long Roche, Yukio Sonoda, Oliver Zivanovic, Ritika Kundra, Agnes Viale, Fatemeh N Derakhshan, Luke Geneslaw, Shirin Issa Bhaloo, Ana Maroldi, Rahelly Nunez, Fresia Pareja, Anthe Stylianou, Mahsa Vahdatinia, Yonina Bykov, Rachel N Grisham, Ying L Liu, Yulia Lakhman, Ines Nikolovski, Daniel Kelly, Jianjiong Gao, Andrea Schietinger, Travis J Hollmann, Samuel F Bakhoum, Robert A Soslow, Lora H Ellenson, Nadeem R Abu-Rustum, Carol Aghajanian, Claire F Friedman, Andrew McPherson, Britta Weigelt, Dmitriy Zamarin, Sohrab P Shah.
      High-grade serous ovarian cancer (HGSOC) is an archetypal cancer of genomic instability1-4 patterned by distinct mutational processes5,6, tumour heterogeneity7-9 and intraperitoneal spread7,8,10. Immunotherapies have had limited efficacy in HGSOC11-13, highlighting an unmet need to assess how mutational processes and the anatomical sites of tumour foci determine the immunological states of the tumour microenvironment. Here we carried out an integrative analysis of whole-genome sequencing, single-cell RNA sequencing, digital histopathology and multiplexed immunofluorescence of 160 tumour sites from 42 treatment-naive patients with HGSOC. Homologous recombination-deficient HRD-Dup (BRCA1 mutant-like) and HRD-Del (BRCA2 mutant-like) tumours harboured inflammatory signalling and ongoing immunoediting, reflected in loss of HLA diversity and tumour infiltration with highly differentiated dysfunctional CD8+ T cells. By contrast, foldback-inversion-bearing tumours exhibited elevated immunosuppressive TGFβ signalling and immune exclusion, with predominantly naive/stem-like and memory T cells. Phenotypic state associations were specific to anatomical sites, highlighting compositional, topological and functional differences between adnexal tumours and distal peritoneal foci. Our findings implicate anatomical sites and mutational processes as determinants of evolutionary phenotypic divergence and immune resistance mechanisms in HGSOC. Our study provides a multi-omic cellular phenotype data substrate from which to develop and interpret future personalized immunotherapeutic approaches and early detection research.
    DOI:  https://doi.org/10.1038/s41586-022-05496-1
  59. JCI Insight. 2022 11 22. pii: e154124. [Epub ahead of print]7(22):
    Single-cell analysis of senescent epithelia reveals targetable mechanisms promoting fibrosis.
    Eoin D O'Sullivan, Katie J Mylonas, Rachel Bell, Cyril Carvalho, David P Baird, Carolynn Cairns, Kevin M Gallagher, Ross Campbell, Marie Docherty, Alexander Laird, Neil C Henderson, Tamir Chandra, Kristina Kirschner, Bryan Conway, Gry H Dihazi, Michael Zeisberg, Jeremy Hughes, Laura Denby, Hassan Dihazi, David A Ferenbach.
      Progressive fibrosis and maladaptive organ repair result in significant morbidity and millions of premature deaths annually. Senescent cells accumulate with aging and after injury and are implicated in organ fibrosis, but the mechanisms by which senescence influences repair are poorly understood. Using 2 murine models of injury and repair, we show that obstructive injury generated senescent epithelia, which persisted after resolution of the original injury, promoted ongoing fibrosis, and impeded adaptive repair. Depletion of senescent cells with ABT-263 reduced fibrosis in reversed ureteric obstruction and after renal ischemia/reperfusion injury. We validated these findings in humans, showing that senescence and fibrosis persisted after relieved renal obstruction. We next characterized senescent epithelia in murine renal injury using single-cell RNA-Seq. We extended our classification to human kidney and liver disease and identified conserved profibrotic proteins, which we validated in vitro and in human disease. We demonstrated that increased levels of protein disulfide isomerase family A member 3 (PDIA3) augmented TGF-β-mediated fibroblast activation. Inhibition of PDIA3 in vivo significantly reduced kidney fibrosis during ongoing renal injury and as such represented a new potential therapeutic pathway. Analysis of the signaling pathways of senescent epithelia connected senescence to organ fibrosis, permitting rational design of antifibrotic therapies.
    Keywords:  Bioinformatics; Cell Biology; Cellular senescence; Fibrosis; Nephrology
    DOI:  https://doi.org/10.1172/jci.insight.154124
  60. Nat Commun. 2022 Dec 12. 13(1): 7682
    Phenome-wide association study of loci harboring de novo tandem repeat mutations in UK Biobank exomes.
    Frank R Wendt, Gita A Pathak, Renato Polimanti.
      When present in coding regions, tandem repeats (TRs) may have large effects on protein structure and function contributing to health and disease. We use a family-based design to identify de novo TRs and assess their impact at the population level in 148,607 European ancestry participants from the UK Biobank. The 427 loci with de novo TR mutations are enriched for targets of microRNA-184 (21.1-fold, P = 4.30 × 10-5, FDR = 9.50 × 10-3). There are 123 TR-phenotype associations with posterior probabilities > 0.95. These relate to body structure, cognition, and cardiovascular, metabolic, psychiatric, and respiratory outcomes. We report several loci with large likely causal effects on tissue microstructure, including the FAN1-[TG]N and carotid intima-media thickness (mean thickness: beta = 5.22, P = 1.22 × 10-6, FDR = 0.004; maximum thickness: beta = 6.44, P = 1.12 × 10-6, FDR = 0.004). Two exonic repeats FNBP4-[GGT]N and BTN2A1-[CCT]N alter protein structure. In this work, we contribute clear and testable hypotheses of dose-dependent TR implications linking genetic variation and protein structure with health and disease outcomes.
    DOI:  https://doi.org/10.1038/s41467-022-35423-x
  61. Nat Commun. 2022 Dec 13. 13(1): 7722
    Condensates formed by prion-like low-complexity domains have small-world network structures and interfaces defined by expanded conformations.
    Mina Farag, Samuel R Cohen, Wade M Borcherds, Anne Bremer, Tanja Mittag, Rohit V Pappu.
      Biomolecular condensates form via coupled associative and segregative phase transitions of multivalent associative macromolecules. Phase separation coupled to percolation is one example of such transitions. Here, we characterize molecular and mesoscale structural descriptions of condensates formed by intrinsically disordered prion-like low complexity domains (PLCDs). These systems conform to sticker-and-spacers architectures. Stickers are cohesive motifs that drive associative interactions through reversible crosslinking and spacers affect the cooperativity of crosslinking and overall macromolecular solubility. Our computations reproduce experimentally measured sequence-specific phase behaviors of PLCDs. Within simulated condensates, networks of reversible inter-sticker crosslinks organize PLCDs into small-world topologies. The overall dimensions of PLCDs vary with spatial location, being most expanded at and preferring to be oriented perpendicular to the interface. Our results demonstrate that even simple condensates with one type of macromolecule feature inhomogeneous spatial organizations of molecules and interfacial features that likely prime them for biochemical activity.
    DOI:  https://doi.org/10.1038/s41467-022-35370-7
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