bims-nimamd Biomed News
on Neuroimmunity and neuroinflammation in ageing and metabolic disease
Issue of 2023–12–17
63 papers selected by
Fawaz Alzaïd, Sorbonne Université
  1. A challenging move.
  2. The support I needed.
  3. Epigenetic memory in 3D.
  4. A nuclear STING in the tail for canonical signalling.
  5. Human and mouse neutrophils share core transcriptional programs in both homeostatic and inflamed contexts.
  6. Mitochondrial- and NOX4-dependent antioxidant defence mitigates progression to non-alcoholic steatohepatitis in obesity.
  7. Single-cell spatial metabolomics with cell-type specific protein profiling for tissue systems biology.
  8. Molecularly defined and spatially resolved cell atlas of the whole mouse brain.
  9. Immunotherapies for Alzheimer's disease.
  10. Are your organs ageing well? The blood holds clues.
  11. Prevention of respiratory virus transmission by resident memory CD8+ T cells.
  12. Stat5 opposes the transcription factor Tox and rewires exhausted CD8+ T cells toward durable effector-like states during chronic antigen exposure.
  13. GRAF1 integrates PINK1-Parkin signaling and actin dynamics to mediate cardiac mitochondrial homeostasis.
  14. A class of secreted mammalian peptides with potential to expand cell-cell communication.
  15. Slide-tags enables single-nucleus barcoding for multimodal spatial genomics.
  16. Nuclear cGAS restricts L1 retrotransposition by promoting TRIM41-mediated ORF2p ubiquitination and degradation.
  17. Rewriting the mammalian genome, one locus at a time.
  18. CENP-A and CENP-B collaborate to create an open centromeric chromatin state.
  19. Epigenetic profiling of cancers using liquid biopsies.
  20. DPPIV+ fibro-adipogenic progenitors form the niche of adult skeletal muscle self-renewing resident macrophages.
  21. Phospholipids are imported into mitochondria by VDAC, a dimeric beta barrel scramblase.
  22. Single-photon microscopy to study biomolecular condensates.
  23. An archetype and scaling of developmental tissue dynamics across species.
  24. IgG and IgM cooperate in coating of intestinal bacteria in IgA deficiency.
  25. Immunoproximity biotinylation reveals the axon initial segment proteome.
  26. How high can the brain compensate.
  27. 'It's all gone': CAR-T therapy forces autoimmune diseases into remission.
  28. Stat5a sobers up inTOXicated T cells.
  29. Antigen-specific memory NK cell responses against HIV and influenza use the NKG2/HLA-E axis.
  30. A transcriptomic taxonomy of mouse brain-wide spinal projecting neurons.
  31. Astrocytic insulin receptor controls circadian behavior via dopamine signaling in a sexually dimorphic manner.
  32. Senescence-associated 13-HODE production promotes age-related liver steatosis by directly inhibiting catalase activity.
  33. Multi-ancestry study of the genetics of problematic alcohol use in over 1 million individuals.
  34. Is Protein BLAST a thing of the past?
  35. Immunomodulatory leptin receptor+ sympathetic perineurial barrier cells protect against obesity by facilitating brown adipose tissue thermogenesis.
  36. Improving equity in patent inventorship.
  37. Argonaute3-SF3B3 complex controls pre-mRNA splicing to restrain type 2 immunity.
  38. The assembly of the Mitochondrial Complex I Assembly complex uncovers a redox pathway coordination.
  39. Downregulation of mitochondrial metabolism is a driver for fast skeletal muscle loss during mouse aging.
  40. Sleep deprivation whips up cytokine storm.
  41. A neuroprosthesis for Parkinson's disease.
  42. Itaconate promotes hepatocellular carcinoma progression by epigenetic induction of CD8+ T-cell exhaustion.
  43. Indigenous diversity in Australia's DNA tapestry unlocked for genetic equity.
  44. Base-editing mutagenesis maps alleles to tune human T cell functions.
  45. No room at the table.
  46. Oxytocin produced by neurons in fat tissue releases stored lipids.
  47. Itaconate suppresses atherosclerosis by activating a Nrf2-dependent anti-inflammatory response in macrophages in mice.
  48. Applying compressed Perturb-seq to genetic screens.
  49. Single-cell analysis of chromatin accessibility in the adult mouse brain.
  50. The mitochondrial ATP synthase is a negative regulator of the mitochondrial permeability transition pore.
  51. Complexities of plastic cleanup.
  52. Lymph node stromal cell responses to perinatal T cell waves, a temporal atlas.
  53. Human-wild bird cooperation.
  54. Control of lipolysis by a population of oxytocinergic sympathetic neurons.
  55. How CRISPR gene editing could help treat Alzheimer's.
  56. Positive results in Alzheimer's disease trials.
  57. Unravelling the mechanism of neurotensin recognition by neurotensin receptor 1.
  58. WHO cautions against non-sugar sweeteners.
  59. Nutrient deprivation alters the rate of COPII subunit recruitment at ER subdomains to tune secretory protein transport.
  60. Seeing through the fog of long COVID.
  61. Anti-VEGFR2 F(ab')2 drug conjugate promotes renal accumulation and glomerular repair in diabetic nephropathy.
  62. Translation for transmission.
  63. Phase-separated CCER1 coordinates the histone-to-protamine transition and male fertility.
  1. Science. 2023 Dec 15. 382(6676): 1322
    A challenging move.
    Adrian Beckert.
      
    DOI:  https://doi.org/10.1126/science.adn4193
  2. Science. 2023 Dec 08. 382(6675): 1198
    The support I needed.
    Theresa Mercer.
      
    DOI:  https://doi.org/10.1126/science.adn2827
  3. Nat Genet. 2023 Dec;55(12): 2019
    Epigenetic memory in 3D.
    Chiara Anania.
      
    DOI:  https://doi.org/10.1038/s41588-023-01615-4
  4. Nat Rev Immunol. 2023 Dec 11.
    A nuclear STING in the tail for canonical signalling.
    Kirsty Minton.
      
    DOI:  https://doi.org/10.1038/s41577-023-00981-8
  5. Nat Commun. 2023 Dec 08. 14(1): 8133
    Human and mouse neutrophils share core transcriptional programs in both homeostatic and inflamed contexts.
    Nicolaj S Hackert, Felix A Radtke, Tarik Exner, Hanns-Martin Lorenz, Carsten Müller-Tidow, Peter A Nigrovic, Guido Wabnitz, Ricardo Grieshaber-Bouyer.
      Neutrophils are frequently studied in mouse models, but the extent to which findings translate to humans remains poorly defined. In an integrative analysis of 11 mouse and 13 human datasets, we find a strong correlation of neutrophil gene expression across species. In inflammation, neutrophils display substantial transcriptional diversity but share a core inflammation program. This program includes genes encoding IL-1 family members, CD14, IL-4R, CD69, and PD-L1. Chromatin accessibility of core inflammation genes increases in blood compared to bone marrow and further in tissue. Transcription factor enrichment analysis implicates members of the NF-κB family and AP-1 complex as important drivers, and HoxB8 neutrophils with JunB knockout show a reduced expression of core inflammation genes in resting and activated cells. In independent single-cell validation data, neutrophil activation by type I or type II interferon, G-CSF, and E. coli leads to upregulation in core inflammation genes. In COVID-19 patients, higher expression of core inflammation genes in neutrophils is associated with more severe disease. In vitro treatment with GM-CSF, LPS, and type II interferon induces surface protein upregulation of core inflammation members. Together, we demonstrate transcriptional conservation in neutrophils in homeostasis and identify a core inflammation program shared across heterogeneous inflammatory conditions.
    DOI:  https://doi.org/10.1038/s41467-023-43573-9
  6. J Clin Invest. 2023 Dec 07. pii: e162533. [Epub ahead of print]
    Mitochondrial- and NOX4-dependent antioxidant defence mitigates progression to non-alcoholic steatohepatitis in obesity.
    Spencer Greatorex, Supreet Kaur, Chrysovalantou E Xirouchaki, Pei Kee Goh, Florian Wiede, Amanda J Genders, Melanie Tran, YaoYao Jia, Arthe Raajendiran, Wendy A Brown, Catriona A McLean, Junichi Sadoshima, Matthew J Watt, Tony Tiganis.
      Non-alcoholic fatty liver disease (NAFLD) is prevalent in the majority of obese individuals, but in a subset, this progresses to non-alcoholic steatohepatitis (NASH) and fibrosis. The mechanisms that prevent NASH and fibrosis in the majority of NAFLD patients remain unclear. Here we report that NAD(P)H oxidase (NOX)-4 and nuclear factor erythroid 2-related factor 2 (NFE2L2) were elevated in hepatocytes early in disease progression to prevent NASH/fibrosis. Mitochondrial-derived reactive oxygen species (ROS) activated NFE2L2 to induce the expression of NOX4, which in turn generated H2O2 to exacerbate the NFE2L2 antioxidant defense response. The deletion or inhibition of NOX4 in hepatocytes decreased ROS and attenuated antioxidant defense to promote mitochondrial oxidative stress, damage proteins and lipids, diminish insulin signalling and promote cell death upon oxidant challenge. Hepatocyte NOX4 deletion in high fat fed obese mice, which otherwise develop steatosis, but not NASH, resulted in hepatic oxidative damage, inflammation and T cell recruitment to drive NASH and fibrosis, whereas NOX4 overexpression tempered the development of NASH/fibrosis in mice fed a NASH-promoting diet. Thus, mitochondrial- and NOX4-derived ROS function in concert to drive a NFE2L2 antioxidant defense response to attenuate oxidative liver damage and the progression to NASH/fibrosis in obesity.
    Keywords:  Diabetes; Glucose metabolism; Hepatology; Metabolism; Obesity
    DOI:  https://doi.org/10.1172/JCI162533
  7. Nat Commun. 2023 Dec 13. 14(1): 8260
    Single-cell spatial metabolomics with cell-type specific protein profiling for tissue systems biology.
    Thomas Hu, Mayar Allam, Shuangyi Cai, Walter Henderson, Brian Yueh, Aybuke Garipcan, Anton V Ievlev, Maryam Afkarian, Semir Beyaz, Ahmet F Coskun.
      Metabolic reprogramming in cancer and immune cells occurs to support their increasing energy needs in biological tissues. Here we propose Single Cell Spatially resolved Metabolic (scSpaMet) framework for joint protein-metabolite profiling of single immune and cancer cells in male human tissues by incorporating untargeted spatial metabolomics and targeted multiplexed protein imaging in a single pipeline. We utilized the scSpaMet to profile cell types and spatial metabolomic maps of 19507, 31156, and 8215 single cells in human lung cancer, tonsil, and endometrium tissues, respectively. The scSpaMet analysis revealed cell type-dependent metabolite profiles and local metabolite competition of neighboring single cells in human tissues. Deep learning-based joint embedding revealed unique metabolite states within cell types. Trajectory inference showed metabolic patterns along cell differentiation paths. Here we show scSpaMet's ability to quantify and visualize the cell-type specific and spatially resolved metabolic-protein mapping as an emerging tool for systems-level understanding of tissue biology.
    DOI:  https://doi.org/10.1038/s41467-023-43917-5
  8. Nature. 2023 Dec;624(7991): 343-354
    Molecularly defined and spatially resolved cell atlas of the whole mouse brain.
    Meng Zhang, Xingjie Pan, Won Jung, Aaron R Halpern, Stephen W Eichhorn, Zhiyun Lei, Limor Cohen, Kimberly A Smith, Bosiljka Tasic, Zizhen Yao, Hongkui Zeng, Xiaowei Zhuang.
      In mammalian brains, millions to billions of cells form complex interaction networks to enable a wide range of functions. The enormous diversity and intricate organization of cells have impeded our understanding of the molecular and cellular basis of brain function. Recent advances in spatially resolved single-cell transcriptomics have enabled systematic mapping of the spatial organization of molecularly defined cell types in complex tissues1-3, including several brain regions (for example, refs. 1-11). However, a comprehensive cell atlas of the whole brain is still missing. Here we imaged a panel of more than 1,100 genes in approximately 10 million cells across the entire adult mouse brains using multiplexed error-robust fluorescence in situ hybridization12 and performed spatially resolved, single-cell expression profiling at the whole-transcriptome scale by integrating multiplexed error-robust fluorescence in situ hybridization and single-cell RNA sequencing data. Using this approach, we generated a comprehensive cell atlas of more than 5,000 transcriptionally distinct cell clusters, belonging to more than 300 major cell types, in the whole mouse brain with high molecular and spatial resolution. Registration of this atlas to the mouse brain common coordinate framework allowed systematic quantifications of the cell-type composition and organization in individual brain regions. We further identified spatial modules characterized by distinct cell-type compositions and spatial gradients featuring gradual changes of cells. Finally, this high-resolution spatial map of cells, each with a transcriptome-wide expression profile, allowed us to infer cell-type-specific interactions between hundreds of cell-type pairs and predict molecular (ligand-receptor) basis and functional implications of these cell-cell interactions. These results provide rich insights into the molecular and cellular architecture of the brain and a foundation for functional investigations of neural circuits and their dysfunction in health and disease.
    DOI:  https://doi.org/10.1038/s41586-023-06808-9
  9. Science. 2023 Dec 15. 382(6676): 1242-1244
    Immunotherapies for Alzheimer's disease.
    Todd E Golde, Allan I Levey.
      Antibodies targeting amyloid-β aggregates slow decline in Alzheimer's disease.
    DOI:  https://doi.org/10.1126/science.adj9255
  10. Nature. 2023 Dec;624(7991): 237-238
    Are your organs ageing well? The blood holds clues.
    Max Kozlov.
      
    Keywords:  Ageing; Diseases; Medical research; Proteomics
    DOI:  https://doi.org/10.1038/d41586-023-03821-w
  11. Nature. 2023 Dec 12.
    Prevention of respiratory virus transmission by resident memory CD8+ T cells.
    Ida Uddbäck, Sarah E Michalets, Ananya Saha, Cameron Mattingly, Kirsten N Kost, M Elliott Williams, Laurel A Lawrence, Sakeenah L Hicks, Anice C Lowen, Hasan Ahmed, Allan R Thomsen, Charles J Russell, Christopher D Scharer, Jeremy M Boss, Katia Koelle, Rustom Antia, Jan P Christensen, Jacob E Kohlmeier.
      An ideal vaccine not only attenuates virus growth and disease in infected individuals but also reduces the spread of infections in the population, thereby generating herd immunity. While this strategy has proven successful by generating humoral immunity to measles, yellow fever and polio, many respiratory viruses evolve to evade pre-existing antibodies 1. One approach for improving the breadth of antiviral immunity against escape variants is through the generation of memory T cells in the respiratory tract, which are positioned to rapidly respond to respiratory virus infections 2-6. However, it is unknown whether memory T cells alone can effectively surveil the respiratory tract to an extent that they eliminate or greatly reduce viral transmission following exposure of an individual to infection. Here, we use a mouse model of natural parainfluenza virus transmission to quantify the extent to which memory CD8 T cells resident in the respiratory tract can provide herd immunity by reducing both the susceptibility of acquiring infection and the extent of transmission, even in the absence of virus-specific antibodies. We demonstrate that protection by resident memory CD8 T cells requires the antiviral cytokine IFN-γ and leads to altered transcriptional programming of epithelial cells within the respiratory tract. These results suggest that tissue-resident CD8 T cells in the respiratory tract can play important roles in both protecting the host against viral disease and in limiting viral spread throughout the population.
    DOI:  https://doi.org/10.1038/s41586-023-06937-1
  12. Immunity. 2023 Dec 12. pii: S1074-7613(23)00487-9. [Epub ahead of print]56(12): 2699-2718.e11
    Stat5 opposes the transcription factor Tox and rewires exhausted CD8+ T cells toward durable effector-like states during chronic antigen exposure.
    Jean-Christophe Beltra, Mohamed S Abdel-Hakeem, Sasikanth Manne, Zhen Zhang, Hua Huang, Makoto Kurachi, Leon Su, Lora Picton, Shin Foong Ngiow, Yuki Muroyama, Valentina Casella, Yinghui J Huang, Josephine R Giles, Divij Mathew, Jonathan Belman, Max Klapholz, Hélène Decaluwe, Alexander C Huang, Shelley L Berger, K Christopher Garcia, E John Wherry.
      Rewiring exhausted CD8+ T (Tex) cells toward functional states remains a therapeutic challenge. Tex cells are epigenetically programmed by the transcription factor Tox. However, epigenetic remodeling occurs as Tex cells transition from progenitor (Texprog) to intermediate (Texint) and terminal (Texterm) subsets, suggesting development flexibility. We examined epigenetic transitions between Tex cell subsets and revealed a reciprocally antagonistic circuit between Stat5a and Tox. Stat5 directed Texint cell formation and re-instigated partial effector biology during this Texprog-to-Texint cell transition. Constitutive Stat5a activity antagonized Tox and rewired CD8+ T cells from exhaustion to a durable effector and/or natural killer (NK)-like state with superior anti-tumor potential. Temporal induction of Stat5 activity in Tex cells using an orthogonal IL-2:IL2Rβ-pair fostered Texint cell accumulation, particularly upon PD-L1 blockade. Re-engaging Stat5 also partially reprogrammed the epigenetic landscape of exhaustion and restored polyfunctionality. These data highlight therapeutic opportunities of manipulating the IL-2-Stat5 axis to rewire Tex cells toward more durably protective states.
    Keywords:  CD8(+) T cell; IL-2; PD-1 blockade; Stat5; Tex intermediate; Tox; epigenetic reprogramming; exhaustion; orthogonal IL-2:IL2Rβ
    DOI:  https://doi.org/10.1016/j.immuni.2023.11.005
  13. Nat Commun. 2023 Dec 11. 14(1): 8187
    GRAF1 integrates PINK1-Parkin signaling and actin dynamics to mediate cardiac mitochondrial homeostasis.
    Qiang Zhu, Matthew E Combs, Juan Liu, Xue Bai, Wenbo B Wang, Laura E Herring, Jiandong Liu, Jason W Locasale, Dawn E Bowles, Ryan T Gross, Michelle Mendiola Pla, Christopher P Mack, Joan M Taylor.
      The serine/threonine kinase, PINK1, and the E3 ubiquitin ligase, Parkin, are known to facilitate LC3-dependent autophagosomal encasement and lysosomal clearance of dysfunctional mitochondria, and defects in this process contribute to a variety of cardiometabolic and neurological diseases. Although recent evidence indicates that dynamic actin remodeling plays an important role in PINK1/Parkin-mediated mitochondrial autophagy (mitophagy), the underlying signaling mechanisms remain unknown. Here, we identify the RhoGAP GRAF1 (Arhgap26) as a PINK1 substrate that regulates mitophagy. GRAF1 promotes the release of damaged mitochondria from F-actin anchors, regulates mitochondrial-associated Arp2/3-mediated actin remodeling and facilitates Parkin-LC3 interactions to enhance mitochondria capture by autophagosomes. Graf1 phosphorylation on PINK1-dependent sites is dysregulated in human heart failure, and cardiomyocyte-restricted Graf1 depletion in mice blunts mitochondrial clearance and attenuates compensatory metabolic adaptations to stress. Overall, we identify GRAF1 as an enzyme that coordinates cytoskeletal and metabolic remodeling to promote cardioprotection.
    DOI:  https://doi.org/10.1038/s41467-023-43889-6
  14. Nat Commun. 2023 Dec 08. 14(1): 8125
    A class of secreted mammalian peptides with potential to expand cell-cell communication.
    Amanda L Wiggenhorn, Hind Z Abuzaid, Laetitia Coassolo, Veronica L Li, Julia T Tanzo, Wei Wei, Xuchao Lyu, Katrin J Svensson, Jonathan Z Long.
      Peptide hormones and neuropeptides are signaling molecules that control diverse aspects of mammalian homeostasis and physiology. Here we provide evidence for the endogenous presence of a sequence diverse class of blood-borne peptides that we call "capped peptides." Capped peptides are fragments of secreted proteins and defined by the presence of two post-translational modifications - N-terminal pyroglutamylation and C-terminal amidation - which function as chemical "caps" of the intervening sequence. Capped peptides share many regulatory characteristics in common with that of other signaling peptides, including dynamic physiologic regulation. One capped peptide, CAP-TAC1, is a tachykinin neuropeptide-like molecule and a nanomolar agonist of mammalian tachykinin receptors. A second capped peptide, CAP-GDF15, is a 12-mer peptide cleaved from the prepropeptide region of full-length GDF15 that, like the canonical GDF15 hormone, also reduces food intake and body weight. Capped peptides are a potentially large class of signaling molecules with potential to broadly regulate cell-cell communication in mammalian physiology.
    DOI:  https://doi.org/10.1038/s41467-023-43857-0
  15. Nature. 2023 Dec 13.
    Slide-tags enables single-nucleus barcoding for multimodal spatial genomics.
    Andrew J C Russell, Jackson A Weir, Naeem M Nadaf, Matthew Shabet, Vipin Kumar, Sandeep Kambhampati, Ruth Raichur, Giovanni J Marrero, Sophia Liu, Karol S Balderrama, Charles R Vanderburg, Vignesh Shanmugam, Luyi Tian, J Bryan Iorgulescu, Charles H Yoon, Catherine J Wu, Evan Z Macosko, Fei Chen.
      Recent technological innovations have enabled the high-throughput quantification of gene expression and epigenetic regulation within individual cells, transforming our understanding of how complex tissues are constructed1-6. However, missing from these measurements is the ability to routinely and easily spatially localize these profiled cells. We developed a strategy, Slide-tags, in which single nuclei within an intact tissue section are tagged with spatial barcode oligonucleotides derived from DNA-barcoded beads with known positions. These tagged nuclei can then be used as an input into a wide variety of single-nucleus profiling assays. Application of Slide-tags to the mouse hippocampus positioned nuclei at less than 10 μm spatial resolution and delivered whole-transcriptome data that are indistinguishable in quality from ordinary single-nucleus RNA-sequencing data. To demonstrate that Slide-tags can be applied to a wide variety of human tissues, we performed the assay on brain, tonsil and melanoma. We revealed cell-type-specific spatially varying gene expression across cortical layers and spatially contextualized receptor-ligand interactions driving B cell maturation in lymphoid tissue. A major benefit of Slide-tags is that it is easily adaptable to almost any single-cell measurement technology. As a proof of principle, we performed multiomic measurements of open chromatin, RNA and T cell receptor (TCR) sequences in the same cells from metastatic melanoma, identifying transcription factor motifs driving cancer cell state transitions in spatially distinct microenvironments. Slide-tags offers a universal platform for importing the compendium of established single-cell measurements into the spatial genomics repertoire.
    DOI:  https://doi.org/10.1038/s41586-023-06837-4
  16. Nat Commun. 2023 Dec 12. 14(1): 8217
    Nuclear cGAS restricts L1 retrotransposition by promoting TRIM41-mediated ORF2p ubiquitination and degradation.
    Zhengyi Zhen, Yu Chen, Haiyan Wang, Huanyin Tang, Haiping Zhang, Haipeng Liu, Ying Jiang, Zhiyong Mao.
      Cyclic GMP-AMP synthase (cGAS), initially identified as a cytosolic DNA sensor, detects DNA fragments to trigger an innate immune response. Recently, accumulating evidence reveals the presence of cGAS within the nucleus. However, the biological functions of nuclear cGAS are not fully understood. Here, we demonstrate that nuclear cGAS represses LINE-1 (L1) retrotransposition to preserve genome integrity in human cells. Mechanistically, the E3 ligase TRIM41 interacts with and ubiquitinates ORF2p to influence its stability, and cGAS enhances the association of ORF2p with TRIM41, thereby promoting TRIM41-mediated ORF2p degradation and the suppression of L1 retrotransposition. In response to DNA damage, cGAS is phosphorylated at serine residues 120 and 305 by CHK2, which promotes cGAS-TRIM41 association, facilitating TRIM41-mediated ORF2p degradation. Moreover, we show that nuclear cGAS mediates the repression of L1 retrotransposition in senescent cells induced by DNA damage agents. We also identify several cancer-associated cGAS mutations that abolish the suppressive effect on L1 retrotransposition by disrupting the CHK2-cGAS-TRIM41-ORF2p regulatory axis. Together, these findings indicate that nuclear cGAS exhibits an inhibitory function in L1 retrotransposition which could provide avenues for future interventions in both aging and tumorigenesis.
    DOI:  https://doi.org/10.1038/s41467-023-43001-y
  17. Nat Genet. 2023 Dec;55(12): 2018
    Rewriting the mammalian genome, one locus at a time.
    Chiara Anania.
      
    DOI:  https://doi.org/10.1038/s41588-023-01617-2
  18. Nat Commun. 2023 Dec 12. 14(1): 8227
    CENP-A and CENP-B collaborate to create an open centromeric chromatin state.
    Harsh Nagpal, Ahmad Ali-Ahmad, Yasuhiro Hirano, Wei Cai, Mario Halic, Tatsuo Fukagawa, Nikolina Sekulić, Beat Fierz.
      Centromeres are epigenetically defined via the presence of the histone H3 variant CENP-A. Contacting CENP-A nucleosomes, the constitutive centromere associated network (CCAN) and the kinetochore assemble, connecting the centromere to spindle microtubules during cell division. The DNA-binding centromeric protein CENP-B is involved in maintaining centromere stability and, together with CENP-A, shapes the centromeric chromatin state. The nanoscale organization of centromeric chromatin is not well understood. Here, we use single-molecule fluorescence and cryoelectron microscopy (cryoEM) to show that CENP-A incorporation establishes a dynamic and open chromatin state. The increased dynamics of CENP-A chromatin create an opening for CENP-B DNA access. In turn, bound CENP-B further opens the chromatin fiber structure and induces nucleosomal DNA unwrapping. Finally, removal of CENP-A increases CENP-B mobility in cells. Together, our studies show that the two centromere-specific proteins collaborate to reshape chromatin structure, enabling the binding of centromeric factors and establishing a centromeric chromatin state.
    DOI:  https://doi.org/10.1038/s41467-023-43739-5
  19. Nat Genet. 2023 Dec;55(12): 2019
    Epigenetic profiling of cancers using liquid biopsies.
    Safia Danovi.
      
    DOI:  https://doi.org/10.1038/s41588-023-01614-5
  20. Nat Commun. 2023 Dec 13. 14(1): 8273
    DPPIV+ fibro-adipogenic progenitors form the niche of adult skeletal muscle self-renewing resident macrophages.
    Farshad Babaeijandaghi, Nasim Kajabadi, Reece Long, Lin Wei Tung, Chun Wai Cheung, Morten Ritso, Chih-Kai Chang, Ryan Cheng, Tiffany Huang, Elena Groppa, Jean X Jiang, Fabio M V Rossi.
      Adult tissue-resident macrophages (RMs) are either maintained by blood monocytes or through self-renewal. While the presence of a nurturing niche is likely crucial to support the survival and function of self-renewing RMs, evidence regarding its nature is limited. Here, we identify fibro-adipogenic progenitors (FAPs) as the main source of colony-stimulating factor 1 (CSF1) in resting skeletal muscle. Using parabiosis in combination with FAP-deficient transgenic mice (PdgfrαCreERT2 × DTA) or mice lacking FAP-derived CSF1 (PdgfrαCreERT2 × Csf1flox/null), we show that local CSF1 from FAPs is required for the survival of both TIM4- monocyte-derived and TIM4+ self-renewing RMs in adult skeletal muscle. The spatial distribution and number of TIM4+ RMs coincide with those of dipeptidyl peptidase IV (DPPIV)+ FAPs, suggesting their role as CSF1-producing niche cells for self-renewing RMs. This finding identifies opportunities to precisely manipulate the function of self-renewing RMs in situ to further unravel their role in health and disease.
    DOI:  https://doi.org/10.1038/s41467-023-43579-3
  21. Nat Commun. 2023 Dec 08. 14(1): 8115
    Phospholipids are imported into mitochondria by VDAC, a dimeric beta barrel scramblase.
    Helene Jahn, Ladislav Bartoš, Grace I Dearden, Jeremy S Dittman, Joost C M Holthuis, Robert Vácha, Anant K Menon.
      Mitochondria are double-membrane-bounded organelles that depend critically on phospholipids supplied by the endoplasmic reticulum. These lipids must cross the outer membrane to support mitochondrial function, but how they do this is unclear. We identify the Voltage Dependent Anion Channel (VDAC), an abundant outer membrane protein, as a scramblase-type lipid transporter that catalyzes lipid entry. On reconstitution into membrane vesicles, dimers of human VDAC1 and VDAC2 catalyze rapid transbilayer translocation of phospholipids by a mechanism that is unrelated to their channel activity. Coarse-grained molecular dynamics simulations of VDAC1 reveal that lipid scrambling occurs at a specific dimer interface where polar residues induce large water defects and bilayer thinning. The rate of phospholipid import into yeast mitochondria is an order of magnitude lower in the absence of VDAC homologs, indicating that VDACs provide the main pathway for lipid entry. Thus, VDAC isoforms, members of a superfamily of beta barrel proteins, moonlight as a class of phospholipid scramblases - distinct from alpha-helical scramblase proteins - that act to import lipids into mitochondria.
    DOI:  https://doi.org/10.1038/s41467-023-43570-y
  22. Nat Commun. 2023 Dec 12. 14(1): 8224
    Single-photon microscopy to study biomolecular condensates.
    Eleonora Perego, Sabrina Zappone, Francesco Castagnetti, Davide Mariani, Erika Vitiello, Jakob Rupert, Elsa Zacco, Gian Gaetano Tartaglia, Irene Bozzoni, Eli Slenders, Giuseppe Vicidomini.
      Biomolecular condensates serve as membrane-less compartments within cells, concentrating proteins and nucleic acids to facilitate precise spatial and temporal orchestration of various biological processes. The diversity of these processes and the substantial variability in condensate characteristics present a formidable challenge for quantifying their molecular dynamics, surpassing the capabilities of conventional microscopy. Here, we show that our single-photon microscope provides a comprehensive live-cell spectroscopy and imaging framework for investigating biomolecular condensation. Leveraging a single-photon detector array, single-photon microscopy enhances the potential of quantitative confocal microscopy by providing access to fluorescence signals at the single-photon level. Our platform incorporates photon spatiotemporal tagging, which allowed us to perform time-lapse super-resolved imaging for molecular sub-diffraction environment organization with simultaneous monitoring of molecular mobility, interactions, and nano-environment properties through fluorescence lifetime fluctuation spectroscopy. This integrated correlative study reveals the dynamics and interactions of RNA-binding proteins involved in forming stress granules, a specific type of biomolecular condensates, across a wide range of spatial and temporal scales. Our versatile framework opens up avenues for exploring a broad spectrum of biomolecular processes beyond the formation of membrane-less organelles.
    DOI:  https://doi.org/10.1038/s41467-023-43969-7
  23. Nat Commun. 2023 Dec 11. 14(1): 8199
    An archetype and scaling of developmental tissue dynamics across species.
    Yoshihiro Morishita, Sang-Woo Lee, Takayuki Suzuki, Hitoshi Yokoyama, Yasuhiro Kamei, Koji Tamura, Aiko Kawasumi-Kita.
      Morphometric studies have revealed the existence of simple geometric relationships among various animal shapes. However, we have little knowledge of the mathematical principles behind the morphogenetic dynamics that form the organ/body shapes of different species. Here, we address this issue by focusing on limb morphogenesis in Gallus gallus domesticus (chicken) and Xenopus laevis (African clawed frog). To compare the deformation dynamics between tissues with different sizes/shapes as well as their developmental rates, we introduce a species-specific rescaled spatial coordinate and a common clock necessary for cross-species synchronization of developmental times. We find that tissue dynamics are well conserved across species under this spacetime coordinate system, at least from the early stages of development through the phase when basic digit patterning is established. For this developmental period, we also reveal that the tissue dynamics of both species are mapped with each other through a time-variant linear transformation in real physical space, from which hypotheses on a species-independent archetype of tissue dynamics and morphogenetic scaling are proposed.
    DOI:  https://doi.org/10.1038/s41467-023-43902-y
  24. Nat Commun. 2023 Dec 08. 14(1): 8124
    IgG and IgM cooperate in coating of intestinal bacteria in IgA deficiency.
    Carsten Eriksen, Janne Marie Moll, Pernille Neve Myers, Ana Rosa Almeida Pinto, Niels Banhos Danneskiold-Samsøe, Rasmus Ibsen Dehli, Lisbeth Buus Rosholm, Marlene Danner Dalgaard, John Penders, Daisy Mae Jonkers, Qiang Pan-Hammarström, Lennart Hammarström, Karsten Kristiansen, Susanne Brix.
      Immunoglobulin A (IgA) is acknowledged to play a role in the defence of the mucosal barrier by coating microorganisms. Surprisingly, IgA-deficient humans exhibit few infection-related complications, raising the question if the more specific IgG may help IgM in compensating for the lack of IgA. Here we employ a cohort of IgA-deficient humans, each paired with IgA-sufficient household members, to investigate multi-Ig bacterial coating. In IgA-deficient humans, IgM alone, and together with IgG, recapitulate coating of most bacterial families, despite an overall 3.6-fold lower Ig-coating. Bacterial IgG coating is dominated by IgG1 and IgG4. Single-IgG2 bacterial coating is sparse and linked to enhanced Escherichia coli load and TNF-α. Although single-IgG2 coating is 1.6-fold more prevalent in IgA deficiency than in healthy controls, it is 2-fold less prevalent than in inflammatory bowel disease. Altogether we demonstrate that IgG assists IgM in coating of most bacterial families in the absence of IgA and identify single-IgG2 bacterial coating as an inflammatory marker.
    DOI:  https://doi.org/10.1038/s41467-023-44007-2
  25. Nat Commun. 2023 Dec 11. 14(1): 8201
    Immunoproximity biotinylation reveals the axon initial segment proteome.
    Wei Zhang, Yu Fu, Luxin Peng, Yuki Ogawa, Xiaoyun Ding, Anne Rasband, Xinyue Zhou, Maya Shelly, Matthew N Rasband, Peng Zou.
      The axon initial segment (AIS) is a specialized neuronal compartment required for action potential generation and neuronal polarity. However, understanding the mechanisms regulating AIS structure and function has been hindered by an incomplete knowledge of its molecular composition. Here, using immuno-proximity biotinylation we further define the AIS proteome and its dynamic changes during neuronal maturation. Among the many AIS proteins identified, we show that SCRIB is highly enriched in the AIS both in vitro and in vivo, and exhibits a periodic architecture like the axonal spectrin-based cytoskeleton. We find that ankyrinG interacts with and recruits SCRIB to the AIS. However, loss of SCRIB has no effect on ankyrinG. This powerful and flexible approach further defines the AIS proteome and provides a rich resource to elucidate the mechanisms regulating AIS structure and function.
    DOI:  https://doi.org/10.1038/s41467-023-44015-2
  26. Nat Neurosci. 2023 Dec 11.
    How high can the brain compensate.
    Jean Mary Zarate.
      
    DOI:  https://doi.org/10.1038/s41593-023-01539-6
  27. Nature. 2023 Dec 12.
    'It's all gone': CAR-T therapy forces autoimmune diseases into remission.
    Heidi Ledford.
      
    Keywords:  Biotechnology; Immunology; Medical research
    DOI:  https://doi.org/10.1038/d41586-023-03968-6
  28. Immunity. 2023 Dec 12. pii: S1074-7613(23)00495-8. [Epub ahead of print]56(12): 2670-2672
    Stat5a sobers up inTOXicated T cells.
    Lara V Donhauser, Dietmar Zehn.
      Exhausted T cells are largely hampered by epigenetically enforced mechanisms that limit their effector potential. In this issue of Immunity, Beltra et al. found that Stat5 can alter these epigenetic profiles when T cells transition from the Tpex precursor stage into differentiated cells. At this stage, enforced Stat5 expression increases the number of intermediate exhausted T cells and induces durable effector cells with superior anti-tumor activity.
    DOI:  https://doi.org/10.1016/j.immuni.2023.11.013
  29. Sci Immunol. 2023 12 08. 8(90): eadi3974
    Antigen-specific memory NK cell responses against HIV and influenza use the NKG2/HLA-E axis.
    Stephanie Jost, Olivier Lucar, Esther Lee, Taylor Yoder, Kyle Kroll, Sho Sugawara, Scott Smith, Rhianna Jones, George Tweet, Alexandra Werner, Phillip J Tomezsko, Haley L Dugan, Joshua Ghofrani, Philippe Rascle, Marcus Altfeld, Michaela Müller-Trutwin, Paul Goepfert, R Keith Reeves.
      Multiple studies have broadened the roles of natural killer (NK) cells functioning as purely innate lymphocytes by demonstrating that they are capable of putative antigen-specific immunological memory against multiple infectious agents including HIV-1 and influenza. However, the mechanisms underlying antigen specificity remain unknown. Here, we demonstrate that antigen-specific human NK cell memory develops upon exposure to both HIV and influenza, unified by a conserved and epitope-specific targetable mechanism largely dependent on the activating CD94/NKG2C receptor and its ligand HLA-E. We validated the permanent acquisition of antigen specificity by individual memory NK cells by single-cell cloning. We identified elevated expression of KLRG1, α4β7, and NKG2C as biomarkers of antigen-specific NK cell memory through complex immunophenotyping. Last, we uncovered individual HLA-E-restricted peptides that may constitute the dominant NK cell response in HIV-1- and influenza-infected persons in vivo. Our findings clarify the mechanisms contributing to antigen-specific memory NK cell responses and suggest that they could be potentially targeted therapeutically for vaccines or other therapeutic interventions.
    DOI:  https://doi.org/10.1126/sciimmunol.adi3974
  30. Nature. 2023 Dec;624(7991): 403-414
    A transcriptomic taxonomy of mouse brain-wide spinal projecting neurons.
    Carla C Winter, Anne Jacobi, Junfeng Su, Leeyup Chung, Cindy T J van Velthoven, Zizhen Yao, Changkyu Lee, Zicong Zhang, Shuguang Yu, Kun Gao, Geraldine Duque Salazar, Evgenii Kegeles, Yu Zhang, Makenzie C Tomihiro, Yiming Zhang, Zhiyun Yang, Junjie Zhu, Jing Tang, Xuan Song, Ryan J Donahue, Qing Wang, Delissa McMillen, Michael Kunst, Ning Wang, Kimberly A Smith, Gabriel E Romero, Michelle M Frank, Alexandra Krol, Riki Kawaguchi, Daniel H Geschwind, Guoping Feng, Lisa V Goodrich, Yuanyuan Liu, Bosiljka Tasic, Hongkui Zeng, Zhigang He.
      The brain controls nearly all bodily functions via spinal projecting neurons (SPNs) that carry command signals from the brain to the spinal cord. However, a comprehensive molecular characterization of brain-wide SPNs is still lacking. Here we transcriptionally profiled a total of 65,002 SPNs, identified 76 region-specific SPN types, and mapped these types into a companion atlas of the whole mouse brain1. This taxonomy reveals a three-component organization of SPNs: (1) molecularly homogeneous excitatory SPNs from the cortex, red nucleus and cerebellum with somatotopic spinal terminations suitable for point-to-point communication; (2) heterogeneous populations in the reticular formation with broad spinal termination patterns, suitable for relaying commands related to the activities of the entire spinal cord; and (3) modulatory neurons expressing slow-acting neurotransmitters and/or neuropeptides in the hypothalamus, midbrain and reticular formation for 'gain setting' of brain-spinal signals. In addition, this atlas revealed a LIM homeobox transcription factor code that parcellates the reticulospinal neurons into five molecularly distinct and spatially segregated populations. Finally, we found transcriptional signatures of a subset of SPNs with large soma size and correlated these with fast-firing electrophysiological properties. Together, this study establishes a comprehensive taxonomy of brain-wide SPNs and provides insight into the functional organization of SPNs in mediating brain control of bodily functions.
    DOI:  https://doi.org/10.1038/s41586-023-06817-8
  31. Nat Commun. 2023 Dec 09. 14(1): 8175
    Astrocytic insulin receptor controls circadian behavior via dopamine signaling in a sexually dimorphic manner.
    Antía González-Vila, María Luengo-Mateos, María Silveira-Loureiro, Pablo Garrido-Gil, Nataliia Ohinska, Marco González-Domínguez, Jose Luis Labandeira-García, Cristina García-Cáceres, Miguel López, Olga Barca-Mayo.
      Mammalian circadian clocks respond to feeding and light cues, adjusting internal rhythms with day/night cycles. Astrocytes serve as circadian timekeepers, driving daily physiological rhythms; however, it's unknown how they ensure precise cycle-to-cycle rhythmicity. This is critical for understanding why mistimed or erratic feeding, as in shift work, disrupts circadian physiology- a condition linked to type 2 diabetes and obesity. Here, we show that astrocytic insulin signaling sets the free-running period of locomotor activity in female mice and food entrainment in male mice. Additionally, ablating the insulin receptor in hypothalamic astrocytes alters cyclic energy homeostasis differently in male and female mice. Remarkably, the mutants exhibit altered dopamine metabolism, and the pharmacological modulation of dopaminergic signaling partially restores distinct circadian traits in both male and female mutant mice. Our findings highlight the role of astrocytic insulin-dopaminergic signaling in conveying time-of-feeding or lighting cues to the astrocyte clock, thus governing circadian behavior in a sex-specific manner.
    DOI:  https://doi.org/10.1038/s41467-023-44039-8
  32. Nat Commun. 2023 Dec 09. 14(1): 8151
    Senescence-associated 13-HODE production promotes age-related liver steatosis by directly inhibiting catalase activity.
    Jinjie Duan, Wenhui Dong, Guangyan Wang, Wenjing Xiu, Guangyin Pu, Jingwen Xu, Chenji Ye, Xu Zhang, Yi Zhu, Chunjiong Wang.
      Aging is a major risk factor for metabolic disorders. Polyunsaturated fatty acid-derived bioactive lipids play critical roles as signaling molecules in metabolic processes. Nonetheless, their effects on age-related liver steatosis remain unknown. Here we show that senescent liver cells induce liver steatosis in a paracrine manner. Linoleic acid-derived 9-hydroxy-octadecadienoic acid (9-HODE) and 13-HODE increase in middle-aged (12-month-old) and aged (20-month-old) male mouse livers and conditioned medium from senescent hepatocytes and macrophages. Arachidonate 15-lipoxygenase, an enzyme for 13-HODE and 9-HODE production, is upregulated in senescent cells. A 9-HODE and 13-HODE mixture induces liver steatosis and activates SREBP1. Furthermore, catalase (CAT) is a direct target of 13-HODE, and its activity is decreased by 13-HODE. CAT overexpression reduces 13-HODE-induced liver steatosis and protects male mice against age-related liver steatosis. Therefore, 13-HODE produced by senescent hepatocytes and macrophages activates SREBP1 by directly inhibiting CAT activity and promotes liver steatosis.
    DOI:  https://doi.org/10.1038/s41467-023-44026-z
  33. Nat Med. 2023 Dec;29(12): 3184-3192
    Multi-ancestry study of the genetics of problematic alcohol use in over 1 million individuals.
    Million Veteran Program
      Problematic alcohol use (PAU), a trait that combines alcohol use disorder and alcohol-related problems assessed with a questionnaire, is a leading cause of death and morbidity worldwide. Here we conducted a large cross-ancestry meta-analysis of PAU in 1,079,947 individuals (European, N = 903,147; African, N = 122,571; Latin American, N = 38,962; East Asian, N = 13,551; and South Asian, N = 1,716 ancestries). We observed a high degree of cross-ancestral similarity in the genetic architecture of PAU and identified 110 independent risk variants in within- and cross-ancestry analyses. Cross-ancestry fine mapping improved the identification of likely causal variants. Prioritizing genes through gene expression and chromatin interaction in brain tissues identified multiple genes associated with PAU. We identified existing medications for potential pharmacological studies by a computational drug repurposing analysis. Cross-ancestry polygenic risk scores showed better performance of association in independent samples than single-ancestry polygenic risk scores. Genetic correlations between PAU and other traits were observed in multiple ancestries, with other substance use traits having the highest correlations. This study advances our knowledge of the genetic etiology of PAU, and these findings may bring possible clinical applicability of genetics insights-together with neuroscience, biology and data science-closer.
    DOI:  https://doi.org/10.1038/s41591-023-02653-5
  34. Nat Commun. 2023 Dec 11. 14(1): 8195
    Is Protein BLAST a thing of the past?
    Ali Al-Fatlawi, Martin Menzel, Michael Schroeder.
      
    DOI:  https://doi.org/10.1038/s41467-023-44082-5
  35. Immunity. 2023 Dec 05. pii: S1074-7613(23)00488-0. [Epub ahead of print]
    Immunomodulatory leptin receptor+ sympathetic perineurial barrier cells protect against obesity by facilitating brown adipose tissue thermogenesis.
    Emma R Haberman, Gitalee Sarker, Bernardo A Arús, Karin A Ziegler, Sandro Meunier, Noelia Martínez-Sánchez, Eliška Freibergerová, Sinem Yilmaz-Özcan, Iara Fernández-González, Chloe Zentai, Conan J O O'Brien, David E Grainger, Davi Sidarta-Oliveira, Svetoslav Chakarov, Andrea Raimondi, Matteo Iannacone, Stefan Engelhardt, Miguel López, Florent Ginhoux, Ana I Domingos.
      Adipose tissues (ATs) are innervated by sympathetic nerves, which drive reduction of fat mass via lipolysis and thermogenesis. Here, we report a population of immunomodulatory leptin receptor-positive (LepR+) sympathetic perineurial barrier cells (SPCs) present in mice and humans, which uniquely co-express Lepr and interleukin-33 (Il33) and ensheath AT sympathetic axon bundles. Brown ATs (BATs) of mice lacking IL-33 in SPCs (SPCΔIl33) had fewer regulatory T (Treg) cells and eosinophils, resulting in increased BAT inflammation. SPCΔIl33 mice were more susceptible to diet-induced obesity, independently of food intake. Furthermore, SPCΔIl33 mice had impaired adaptive thermogenesis and were unresponsive to leptin-induced rescue of metabolic adaptation. We therefore identify LepR+ SPCs as a source of IL-33, which orchestrate an anti-inflammatory BAT environment, preserving sympathetic-mediated thermogenesis and body weight homeostasis. LepR+IL-33+ SPCs provide a cellular link between leptin and immune regulation of body weight, unifying neuroendocrinology and immunometabolism as previously disconnected fields of obesity research.
    Keywords:  IL-33; Tregs; brown adipose tissue; eosinophils; leptin receptor; obesity; perineurial cells; sympathetic nerves; thermogenesis
    DOI:  https://doi.org/10.1016/j.immuni.2023.11.006
  36. Science. 2023 Dec 08. 382(6675): 1128-1129
    Improving equity in patent inventorship.
    Colleen V Chien, Lisa Larrimore Ouellette.
      Expanding who gets credit for invention may boost participation in innovation.
    DOI:  https://doi.org/10.1126/science.adj2911
  37. Cell Rep. 2023 Dec 13. pii: S2211-1247(23)01527-9. [Epub ahead of print]42(12): 113515
    Argonaute3-SF3B3 complex controls pre-mRNA splicing to restrain type 2 immunity.
    Riccardo Guidi, Christopher Wedeles, Daqi Xu, Krzysztof Kolmus, Sarah E Headland, Grace Teng, Joseph Guillory, Yi Jimmy Zeng, Tommy K Cheung, Subhra Chaudhuri, Zora Modrusan, Yuxin Liang, Stuart Horswell, Benjamin Haley, Sascha Rutz, Christopher Rose, Yvonne Franke, Donald S Kirkpatrick, Jason A Hackney, Mark S Wilson.
      Argonaute (AGO) proteins execute microRNA (miRNA)-mediated gene silencing. However, it is unclear whether all 4 mammalian AGO proteins (AGO1, AGO2, AGO3, and AGO4) are required for miRNA activity. We generate Ago1, Ago3, and Ago4-deficient mice (Ago134Δ) and find AGO1/3/4 to be redundant for miRNA biogenesis, homeostasis, or function, a role that is carried out by AGO2. Instead, AGO1/3/4 regulate the expansion of type 2 immunity via precursor mRNA splicing in CD4+ T helper (Th) lymphocytes. Gain- and loss-of-function experiments demonstrate that nuclear AGO3 interacts directly with SF3B3, a component of the U2 spliceosome complex, to aid global mRNA splicing, and in particular the isoforms of the gene Nisch, resulting in a dysregulated Nisch isoform ratio. This work uncouples AGO1, AGO3, and AGO4 from miRNA-mediated RNA interference, identifies an AGO3:SF3B3 complex in the nucleus, and reveals a mechanism by which AGO proteins regulate inflammatory diseases.
    Keywords:  CP: Immunology; CP: Molecular biology; IL-13; RNAi; T cell; T(H)2; allergy; eosinophil; gene regulation; helminth; lymphocyte; miRNA
    DOI:  https://doi.org/10.1016/j.celrep.2023.113515
  38. Nat Commun. 2023 Dec 12. 14(1): 8248
    The assembly of the Mitochondrial Complex I Assembly complex uncovers a redox pathway coordination.
    Lindsay McGregor, Samira Acajjaoui, Ambroise Desfosses, Melissa Saïdi, Maria Bacia-Verloop, Jennifer J Schwarz, Pauline Juyoux, Jill von Velsen, Matthew W Bowler, Andrew A McCarthy, Eaazhisai Kandiah, Irina Gutsche, Montserrat Soler-Lopez.
      The Mitochondrial Complex I Assembly (MCIA) complex is essential for the biogenesis of respiratory Complex I (CI), the first enzyme in the respiratory chain, which has been linked to Alzheimer's disease (AD) pathogenesis. However, how MCIA facilitates CI assembly, and how it is linked with AD pathogenesis, is poorly understood. Here we report the structural basis of the complex formation between the MCIA subunits ECSIT and ACAD9. ECSIT binding induces a major conformational change in the FAD-binding loop of ACAD9, releasing the FAD cofactor and converting ACAD9 from a fatty acid β-oxidation (FAO) enzyme to a CI assembly factor. We provide evidence that ECSIT phosphorylation downregulates its association with ACAD9 and is reduced in neuronal cells upon exposure to amyloid-β (Aβ) oligomers. These findings advance our understanding of the MCIA complex assembly and suggest a possible role for ECSIT in the reprogramming of bioenergetic pathways linked to Aβ toxicity, a hallmark of AD.
    DOI:  https://doi.org/10.1038/s41467-023-43865-0
  39. Commun Biol. 2023 Dec 08. 6(1): 1240
    Downregulation of mitochondrial metabolism is a driver for fast skeletal muscle loss during mouse aging.
    Raquel Fernando, Anastasia V Shindyapina, Mario Ost, Didac Santesmasses, Yan Hu, Alexander Tyshkovskiy, Sun Hee Yim, Jürgen Weiss, Vadim N Gladyshev, Tilman Grune, José Pedro Castro.
      Skeletal muscle aging is characterized by the loss of muscle mass, strength and function, mainly attributed to the atrophy of glycolytic fibers. Underlying mechanisms driving the skeletal muscle functional impairment are yet to be elucidated. To unbiasedly uncover its molecular mechanisms, we recurred to gene expression and metabolite profiling in a glycolytic muscle, Extensor digitorum longus (EDL), from young and aged C57BL/6JRj mice. Employing multi-omics approaches we found that the main age-related changes are connected to mitochondria, exhibiting a downregulation in mitochondrial processes. Consistent is the altered mitochondrial morphology. We further compared our mouse EDL aging signature with human data from the GTEx database, reinforcing the idea that our model may recapitulate muscle loss in humans. We are able to show that age-related mitochondrial downregulation is likely to be detrimental, as gene expression signatures from commonly used lifespan extending interventions displayed the opposite direction compared to our EDL aging signature.
    DOI:  https://doi.org/10.1038/s42003-023-05595-3
  40. Nat Rev Immunol. 2023 Dec 11.
    Sleep deprivation whips up cytokine storm.
    Alexandra Flemming.
      
    DOI:  https://doi.org/10.1038/s41577-023-00980-9
  41. Nat Biotechnol. 2023 Dec;41(12): 1689
    A neuroprosthesis for Parkinson's disease.
    Anahita Bishop.
      
    DOI:  https://doi.org/10.1038/s41587-023-02067-1
  42. Nat Commun. 2023 Dec 09. 14(1): 8154
    Itaconate promotes hepatocellular carcinoma progression by epigenetic induction of CD8+ T-cell exhaustion.
    Xuemei Gu, Haoran Wei, Caixia Suo, Shengqi Shen, Chuxu Zhu, Liang Chen, Kai Yan, Zhikun Li, Zhenhua Bian, Pinggen Zhang, Mengqiu Yuan, Yingxuan Yu, Jinzhi Du, Huafeng Zhang, Linchong Sun, Ping Gao.
      Itaconate is a well-known immunomodulatory metabolite; however, its role in hepatocellular carcinoma (HCC) remains unclear. Here, we find that macrophage-derived itaconate promotes HCC by epigenetic induction of Eomesodermin (EOMES)-mediated CD8+ T-cell exhaustion. Our results show that the knockout of immune-responsive gene 1 (IRG1), responsible for itaconate production, suppresses HCC progression. Irg1 knockout leads to a decreased proportion of PD-1+ and TIM-3+ CD8+ T cells. Deletion or adoptive transfer of CD8+ T cells shows that IRG1-promoted tumorigenesis depends on CD8+ T-cell exhaustion. Mechanistically, itaconate upregulates PD-1 and TIM-3 expression levels by promoting succinate-dependent H3K4me3 of the Eomes promoter. Finally, ibuprofen is found to inhibit HCC progression by targeting IRG1/itaconate-dependent tumor immunoevasion, and high IRG1 expression in macrophages predicts poor prognosis in HCC patients. Taken together, our results uncover an epigenetic link between itaconate and HCC and suggest that targeting IRG1 or itaconate might be a promising strategy for HCC treatment.
    DOI:  https://doi.org/10.1038/s41467-023-43988-4
  43. Nature. 2023 Dec 13.
    Indigenous diversity in Australia's DNA tapestry unlocked for genetic equity.
    Katrina G Claw, Amber Nashoba.
      
    Keywords:  Genetics; Genomics
    DOI:  https://doi.org/10.1038/d41586-023-03785-x
  44. Nature. 2023 Dec 13.
    Base-editing mutagenesis maps alleles to tune human T cell functions.
    Ralf Schmidt, Carl C Ward, Rama Dajani, Zev Armour-Garb, Mineto Ota, Vincent Allain, Rosmely Hernandez, Madeline Layeghi, Galen Xing, Laine Goudy, Dmytro Dorovskyi, Charlotte Wang, Yan Yi Chen, Chun Jimmie Ye, Brian R Shy, Luke A Gilbert, Justin Eyquem, Jonathan K Pritchard, Stacie E Dodgson, Alexander Marson.
      CRISPR-enabled screening is a powerful tool for the discovery of genes that control T cell function and has nominated candidate targets for immunotherapies1-6. However, new approaches are required to probe specific nucleotide sequences within key genes. Systematic mutagenesis in primary human T cells could reveal alleles that tune specific phenotypes. DNA base editors are powerful tools for introducing targeted mutations with high efficiency7,8. Here we develop a large-scale base-editing mutagenesis platform with the goal of pinpointing nucleotides that encode amino acid residues that tune primary human T cell activation responses. We generated a library of around 117,000 single guide RNA molecules targeting base editors to protein-coding sites across 385 genes implicated in T cell function and systematically identified protein domains and specific amino acid residues that regulate T cell activation and cytokine production. We found a broad spectrum of alleles with variants encoding critical residues in proteins including PIK3CD, VAV1, LCP2, PLCG1 and DGKZ, including both gain-of-function and loss-of-function mutations. We validated the functional effects of many alleles and further demonstrated that base-editing hits could positively and negatively tune T cell cytotoxic function. Finally, higher-resolution screening using a base editor with relaxed protospacer-adjacent motif requirements9 (NG versus NGG) revealed specific structural domains and protein-protein interaction sites that can be targeted to tune T cell functions. Base-editing screens in primary immune cells thus provide biochemical insights with the potential to accelerate immunotherapy design.
    DOI:  https://doi.org/10.1038/s41586-023-06835-6
  45. Science. 2023 Dec 15. 382(6676): 1244-1245
    No room at the table.
    Lauren C Radlinski, Andreas J Bäumler.
      The gut microbiota prevents infection by crowding out pathogens.
    DOI:  https://doi.org/10.1126/science.adl5891
  46. Nature. 2023 Dec 13.
    Oxytocin produced by neurons in fat tissue releases stored lipids.
      
    Keywords:  Metabolism
    DOI:  https://doi.org/10.1038/d41586-023-03830-9
  47. J Clin Invest. 2023 Dec 12. pii: e173034. [Epub ahead of print]
    Itaconate suppresses atherosclerosis by activating a Nrf2-dependent anti-inflammatory response in macrophages in mice.
    Jianrui Song, Yanling Zhang, Ryan A Frieler, Anthony Andren, Sherri C Wood, Daniel J Tyrrell, Peter Sajjakulnukit, Jane C Deng, Costas A Lyssiotis, Richard M Mortensen, Morgan Salmon, Daniel R Goldstein.
      Itaconate has emerged as a critical immunoregulatory metabolite. Here, we examined the therapeutic potential of itaconate in atherosclerosis. We found that both itaconate and the enzyme that synthesizes it, aconitate decarboxylase 1 (Acod1, also known as "immune-responsive gene 1"/IRG1) are upregulated during atherogenesis in mice. Deletion of Acod1 in myeloid cells exacerbated inflammation and atherosclerosis in vivo and resulted in an elevated frequency of a specific subset of M1-polarized proinflammatory macrophages in the atherosclerotic aorta. Importantly, Acod1 levels were inversely correlated with clinical occlusion in atherosclerotic human aorta specimens. Treating mice with the itaconate derivative 4-ocytyl itaconate attenuated inflammation and atherosclerosis induced by high cholesterol. Mechanistically, we found that the antioxidant transcription factor, Nuclear factor erythroid-2 Related Factor 2 (Nrf2) was required for itaconate to suppress macrophage activation induced by oxidized lipids in vitro and to decrease atherosclerotic lesion areas in vivo. Overall, our work shows that itaconate suppresses atherogenesis by inducing Nrf2-dependent inhibition of proinflammatory responses in macrophages. Activation of the itaconate pathway may represent an important approach to treat atherosclerosis.
    Keywords:  Atherosclerosis; Cardiology; Cardiovascular disease; Inflammation; Macrophages
    DOI:  https://doi.org/10.1172/JCI173034
  48. Nat Genet. 2023 Dec;55(12): 2020
    Applying compressed Perturb-seq to genetic screens.
    Wei Li.
      
    DOI:  https://doi.org/10.1038/s41588-023-01613-6
  49. Nature. 2023 Dec;624(7991): 378-389
    Single-cell analysis of chromatin accessibility in the adult mouse brain.
    Songpeng Zu, Yang Eric Li, Kangli Wang, Ethan J Armand, Sainath Mamde, Maria Luisa Amaral, Yuelai Wang, Andre Chu, Yang Xie, Michael Miller, Jie Xu, Zhaoning Wang, Kai Zhang, Bojing Jia, Xiaomeng Hou, Lin Lin, Qian Yang, Seoyeon Lee, Bin Li, Samantha Kuan, Hanqing Liu, Jingtian Zhou, Antonio Pinto-Duarte, Jacinta Lucero, Julia Osteen, Michael Nunn, Kimberly A Smith, Bosiljka Tasic, Zizhen Yao, Hongkui Zeng, Zihan Wang, Jingbo Shang, M Margarita Behrens, Joseph R Ecker, Allen Wang, Sebastian Preissl, Bing Ren.
      Recent advances in single-cell technologies have led to the discovery of thousands of brain cell types; however, our understanding of the gene regulatory programs in these cell types is far from complete1-4. Here we report a comprehensive atlas of candidate cis-regulatory DNA elements (cCREs) in the adult mouse brain, generated by analysing chromatin accessibility in 2.3 million individual brain cells from 117 anatomical dissections. The atlas includes approximately 1 million cCREs and their chromatin accessibility across 1,482 distinct brain cell populations, adding over 446,000 cCREs to the most recent such annotation in the mouse genome. The mouse brain cCREs are moderately conserved in the human brain. The mouse-specific cCREs-specifically, those identified from a subset of cortical excitatory neurons-are strongly enriched for transposable elements, suggesting a potential role for transposable elements in the emergence of new regulatory programs and neuronal diversity. Finally, we infer the gene regulatory networks in over 260 subclasses of mouse brain cells and develop deep-learning models to predict the activities of gene regulatory elements in different brain cell types from the DNA sequence alone. Our results provide a resource for the analysis of cell-type-specific gene regulation programs in both mouse and human brains.
    DOI:  https://doi.org/10.1038/s41586-023-06824-9
  50. Proc Natl Acad Sci U S A. 2023 Dec 19. 120(51): e2303713120
    The mitochondrial ATP synthase is a negative regulator of the mitochondrial permeability transition pore.
    Ryan Pekson, Felix G Liang, Joshua L Axelrod, Jaehoon Lee, Dongze Qin, Andre J H Wittig, Victor M Paulino, Min Zheng, Pablo M Peixoto, Richard N Kitsis.
      The mitochondrial permeability transition pore (mPTP) is a channel in the inner mitochondrial membrane whose sustained opening in response to elevated mitochondrial matrix Ca2+ concentrations triggers necrotic cell death. The molecular identity of mPTP is unknown. One proposed candidate is the mitochondrial ATP synthase, whose canonical function is to generate most ATP in multicellular organisms. Here, we present mitochondrial, cellular, and in vivo evidence that, rather than serving as mPTP, the mitochondrial ATP synthase inhibits this pore. Our studies confirm previous work showing persistence of mPTP in HAP1 cell lines lacking an assembled mitochondrial ATP synthase. Unexpectedly, however, we observe that Ca2+-induced pore opening is markedly sensitized by loss of the mitochondrial ATP synthase. Further, mPTP opening in cells lacking the mitochondrial ATP synthase is desensitized by pharmacological inhibition and genetic depletion of the mitochondrial cis-trans prolyl isomerase cyclophilin D as in wild-type cells, indicating that cyclophilin D can modulate mPTP through substrates other than subunits in the assembled mitochondrial ATP synthase. Mitoplast patch clamping studies showed that mPTP channel conductance was unaffected by loss of the mitochondrial ATP synthase but still blocked by cyclophilin D inhibition. Cardiac mitochondria from mice whose heart muscle cells we engineered deficient in the mitochondrial ATP synthase also demonstrate sensitization of Ca2+-induced mPTP opening and desensitization by cyclophilin D inhibition. Further, these mice exhibit strikingly larger myocardial infarctions when challenged with ischemia/reperfusion in vivo. We conclude that the mitochondrial ATP synthase does not function as mPTP and instead negatively regulates this pore.
    Keywords:  mitochondrial ATP synthase; mitochondrial permeability transition pore; necrosis
    DOI:  https://doi.org/10.1073/pnas.2303713120
  51. Science. 2023 Dec 08. 382(6675): 1131
    Complexities of plastic cleanup.
      
    DOI:  https://doi.org/10.1126/science.adn2157
  52. Proc Natl Acad Sci U S A. 2023 Dec 19. 120(51): e2316957120
    Lymph node stromal cell responses to perinatal T cell waves, a temporal atlas.
    Teshika Jayewickreme, Christophe Benoist, Diane Mathis.
      The perinatal period is a critical time window in establishing T cell tolerance. Regulatory T cells (Tregs) made during the first 2 wk of life are key drivers of perinatal tolerance induction, but how these cells are generated and operate has not been established. To elucidate the unique environment murine perinatal Tregs encounter within the lymph nodes (LNs) as they first emerge from the thymus, and how it evolves over the succeeding days, we employed single-cell RNA sequencing to generate an atlas of the early LN niche. A highly dynamic picture emerged, the stromal cell compartment showing the most striking changes and putative interactions with other LN cell compartments. In particular, LN stromal cells showed increasing potential for lymphocyte interactions with age. Analogous studies on mice lacking α:β T cells or enriched for autoreactive α:β T cells revealed an acute stromal cell response to α:β T cell dysfunction, largely reflecting dysregulation of Tregs. Punctual ablation of perinatal Tregs induced stromal cell activation that was dependent on both interferon-gamma signaling and activation of conventional CD4+ T cells. These findings elucidate some of the earliest cellular and molecular events in perinatal induction of T cell tolerance, providing a framework for future explorations.
    Keywords:  T cell; interferon; neonatal; regulatory T cell
    DOI:  https://doi.org/10.1073/pnas.2316957120
  53. Science. 2023 Dec 08. 382(6675): 1124-1125
    Human-wild bird cooperation.
    William A Searcy, Stephen Nowicki.
      Honeyguides learn distinct signals made by honey hunters from different cultures.
    DOI:  https://doi.org/10.1126/science.adl5923
  54. Nature. 2023 Dec 13.
    Control of lipolysis by a population of oxytocinergic sympathetic neurons.
    Erwei Li, Luhong Wang, Daqing Wang, Jingyi Chi, Zeran Lin, Gordon I Smith, Samuel Klein, Paul Cohen, Evan D Rosen.
      Oxytocin (OXT), a nine-amino-acid peptide produced in the hypothalamus and released by the posterior pituitary, has well-known actions in parturition, lactation and social behaviour1, and has become an intriguing therapeutic target for conditions such as autism and schizophrenia2. Exogenous OXT has also been shown to have effects on body weight, lipid levels and glucose homeostasis1,3, suggesting that it may also have therapeutic potential for metabolic disease1,4. It is unclear, however, whether endogenous OXT participates in metabolic homeostasis. Here we show that OXT is a critical regulator of adipose tissue lipolysis in both mice and humans. In addition, OXT serves to facilitate the ability of β-adrenergic agonists to fully promote lipolysis. Most surprisingly, the relevant source of OXT in these metabolic actions is a previously unidentified subpopulation of tyrosine hydroxylase-positive sympathetic neurons. Our data reveal that OXT from the peripheral nervous system is an endogenous regulator of adipose and systemic metabolism.
    DOI:  https://doi.org/10.1038/s41586-023-06830-x
  55. Nature. 2023 Dec 11.
    How CRISPR gene editing could help treat Alzheimer's.
    Tosin Thompson.
      
    Keywords:  Alzheimer's disease; Brain; CRISPR-Cas9 genome editing; Gene therapy
    DOI:  https://doi.org/10.1038/d41586-023-03931-5
  56. Nat Med. 2023 Dec;29(12): 2973
    Positive results in Alzheimer's disease trials.
    Karen O'Leary.
      
    DOI:  https://doi.org/10.1038/s41591-023-02709-6
  57. Nat Commun. 2023 Dec 09. 14(1): 8155
    Unravelling the mechanism of neurotensin recognition by neurotensin receptor 1.
    Kazem Asadollahi, Sunnia Rajput, Lazarus Andrew de Zhang, Ching-Seng Ang, Shuai Nie, Nicholas A Williamson, Michael D W Griffin, Ross A D Bathgate, Daniel J Scott, Thomas R Weikl, Guy N L Jameson, Paul R Gooley.
      The conformational ensembles of G protein-coupled receptors (GPCRs) include inactive and active states. Spectroscopy techniques, including NMR, show that agonists, antagonists and other ligands shift the ensemble toward specific states depending on the pharmacological efficacy of the ligand. How receptors recognize ligands and the kinetic mechanism underlying this population shift is poorly understood. Here, we investigate the kinetic mechanism of neurotensin recognition by neurotensin receptor 1 (NTS1) using 19F-NMR, hydrogen-deuterium exchange mass spectrometry and stopped-flow fluorescence spectroscopy. Our results indicate slow-exchanging conformational heterogeneity on the extracellular surface of ligand-bound NTS1. Numerical analysis of the kinetic data of neurotensin binding to NTS1 shows that ligand recognition follows an induced-fit mechanism, in which conformational changes occur after neurotensin binding. This approach is applicable to other GPCRs to provide insight into the kinetic regulation of ligand recognition by GPCRs.
    DOI:  https://doi.org/10.1038/s41467-023-44010-7
  58. Nat Med. 2023 Dec;29(12): 2972
    WHO cautions against non-sugar sweeteners.
    Karen O'Leary.
      
    DOI:  https://doi.org/10.1038/s41591-023-02706-9
  59. Nat Commun. 2023 Dec 08. 14(1): 8140
    Nutrient deprivation alters the rate of COPII subunit recruitment at ER subdomains to tune secretory protein transport.
    William Kasberg, Peter Luong, Kevin A Swift, Anjon Audhya.
      Co-assembly of the multilayered coat protein complex II (COPII) with the Sar1 GTPase at subdomains of the endoplasmic reticulum (ER) enables secretory cargoes to be concentrated efficiently within nascent transport intermediates, which subsequently deliver their contents to ER-Golgi intermediate compartments. Here, we define the spatiotemporal accumulation of native COPII subunits and secretory cargoes at ER subdomains under differing nutrient availability conditions using a combination of CRISPR/Cas9-mediated genome editing and live cell imaging. Our findings demonstrate that the rate of inner COPII coat recruitment serves as a determinant for the pace of cargo export, irrespective of COPII subunit expression levels. Moreover, increasing inner COPII coat recruitment kinetics is sufficient to rescue cargo trafficking deficits caused by acute nutrient limitation. Our findings are consistent with a model in which the rate of inner COPII coat addition acts as an important control point to regulate cargo export from the ER.
    DOI:  https://doi.org/10.1038/s41467-023-44002-7
  60. Nat Med. 2023 Dec;29(12): 2973
    Seeing through the fog of long COVID.
    Karen O'Leary.
      
    DOI:  https://doi.org/10.1038/s41591-023-02713-w
  61. Nat Commun. 2023 Dec 13. 14(1): 8268
    Anti-VEGFR2 F(ab')2 drug conjugate promotes renal accumulation and glomerular repair in diabetic nephropathy.
    Di Liu, Yanling Song, Hui Chen, Yuchan You, Luwen Zhu, Jucong Zhang, Xinyi Xu, Jiahao Hu, Xiajie Huang, Xiaochuan Wu, Xiaoling Xu, Saiping Jiang, Yongzhong Du.
      Poor renal distribution of antibody-based drugs is the key factor contributing to low treatment efficiency for renal diseases and side effects. Here, we prepare F(ab')2 fragmented vascular endothelial growth factor receptor 2 antibody (anti-VEGFR2 (F(ab')2) to block VEGFR2 overactivation in diabetic nephropathy (DN). We find that the anti-VEGFR2 F(ab')2 has a higher accumulation in DN male mice kidneys than the intact VEGFR2 antibody, and simultaneously preserves the binding ability to VEGFR2. Furthermore, we develop an antibody fragment drug conjugate, anti-VEGFR2 F(ab')2-SS31, comprising the anti-VEGFR2 F(ab')2 fragment linked to the mitochondria-targeted antioxidant peptide SS31. We find that introduction of SS31 potentiates the efficacy of anti-VEGFR2 F(ab')2. These findings provide proof of concept for the premise that antibody fragment drug conjugate improves renal distribution and merits drug validation in renal disease therapy.
    DOI:  https://doi.org/10.1038/s41467-023-43847-2
  62. Nat Neurosci. 2023 Dec 11.
    Translation for transmission.
    Shari Wiseman.
      
    DOI:  https://doi.org/10.1038/s41593-023-01541-y
  63. Nat Commun. 2023 Dec 11. 14(1): 8209
    Phase-separated CCER1 coordinates the histone-to-protamine transition and male fertility.
    Dongdong Qin, Yayun Gu, Yu Zhang, Shu Wang, Tao Jiang, Yao Wang, Cheng Wang, Chang Chen, Tao Zhang, Weiya Xu, Hanben Wang, Ke Zhang, Liangjun Hu, Lufan Li, Wei Xie, Xin Wu, Zhibin Hu.
      Idiopathic fertility disorders are associated with mutations in various genes. Here, we report that coiled-coil glutamate-rich protein 1 (CCER1), a germline-specific and intrinsically disordered protein (IDP), mediates postmeiotic spermatid differentiation. In contrast, CCER1 deficiency results in defective sperm chromatin compaction and infertility in mice. CCER1 increases transition protein (Tnp1/2) and protamine (Prm1/2) transcription and mediates multiple histone epigenetic modifications during the histone-to-protamine (HTP) transition. Immiscible with heterochromatin in the nucleus, CCER1 self-assembles into a polymer droplet and forms a liquid-liquid phase-separated condensate in the nucleus. Notably, we identified loss-of-function (LoF) variants of human CCER1 (hCCER1) in five patients with nonobstructive azoospermia (NOA) that were absent in 2713 fertile controls. The mutants led to premature termination or frameshift in CCER1 translation, and disrupted condensates in vitro. In conclusion, we propose that nuclear CCER1 is a phase-separated condensate that links histone epigenetic modifications, HTP transitions, chromatin condensation, and male fertility.
    DOI:  https://doi.org/10.1038/s41467-023-43480-z
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