bims-nimamd Biomed News
on Neuroimmunity and neuroinflammation in ageing and metabolic disease
Issue of 2023–11–12
forty-nine papers selected by
Fawaz Alzaïd, Sorbonne Université
  1. Foxp3 orchestrates reorganization of chromatin architecture to establish regulatory T cell identity.
  2. IL-27 gives a good gut feeling about immune regulation.
  3. Latent human herpesvirus 6 is reactivated in CAR T cells.
  4. Integrative analysis reveals a conserved role for the amyloid precursor protein in proteostasis during aging.
  5. Cryo-electron tomography of NLRP3-activated ASC complexes reveals organelle co-localization.
  6. Selective IL-27 production by intestinal regulatory T cells permits gut-specific regulation of TH17 cell immunity.
  7. Transcriptional reprogramming by mutated IRF4 in lymphoma.
  8. The alarmin IL33 orchestrates type 2 immune-mediated control of thymus regeneration.
  9. Lipid metabolism extinguishes cGAS-STING-induced inflammation.
  10. Tissue-resident B cells orchestrate macrophage polarisation and function.
  11. Alternative lengthening of telomeres (ALT) cells viability is dependent on C-rich telomeric RNAs.
  12. Single-cell genomics reveals region-specific developmental trajectories underlying neuronal diversity in the human hypothalamus.
  13. Transcriptional repression of beige fat innervation via a YAP/TAZ-S100B axis.
  14. A distinct subtype of stromal cell orchestrates the inflammatory response to tissue injury.
  15. Scarless healing.
  16. Global identification of SWI/SNF targets reveals compensation by EP400.
  17. Cryo-EM structures of human magnesium channel MRS2 reveal gating and regulatory mechanisms.
  18. Spatial and single-cell profiling of the metabolome, transcriptome and epigenome of the aging mouse liver.
  19. Themis2 regulates natural killer cell memory function and formation.
  20. AI that reads brain scans shows promise for finding Alzheimer's genes.
  21. The CRTC-1 transcriptional domain is required for COMPASS complex-mediated longevity in C. elegans.
  22. Bacteria tag tumours for CAR T cell attack.
  23. FMRP phosphorylation modulates neuronal translation through YTHDF1.
  24. Structures of the DarR transcription regulator reveal unique modes of second messenger and DNA binding.
  25. Deconstruction of rheumatoid arthritis synovium defines inflammatory subtypes.
  26. Functional alterations of the prefrontal circuit underlying cognitive aging in mice.
  27. Condensing to target RNAs.
  28. Spatial-linked alignment tool (SLAT) for aligning heterogenous slices.
  29. Essential requirement for IER3IP1 in B cell development.
  30. SIKs Regulate HDAC7 Stabilization and Cytokine Recall in Late-Stage T Cell Effector Differentiation.
  31. Sperm bud mitochondria to adjust the numbers.
  32. Cell volume controlled by LRRC8A-formed volume-regulated anion channels fine-tunes T cell activation and function.
  33. A combined adjuvant approach primes robust germinal center responses and humoral immunity in non-human primates.
  34. A method to identify regulators of senolysis.
  35. Gasdermin D permeabilization of mitochondrial inner and outer membranes accelerates and enhances pyroptosis.
  36. Editorial expression of concern.
  37. Lipofuscin-like autofluorescence within microglia and its impact on studying microglial engulfment.
  38. Mitopherogenesis, a form of mitochondria-specific ectocytosis, regulates sperm mitochondrial quantity and fertility.
  39. DNAJB6 mutants display toxic gain of function through unregulated interaction with Hsp70 chaperones.
  40. Systemic and intrinsic functions of ATRX in glial cell fate and CNS myelination in male mice.
  41. Zfp281 and Zfp148 control CD4+ T cell thymic development and TH2 functions.
  42. Regulatory T cell-derived IL-1Ra suppresses the innate response to respiratory viral infection.
  43. GATA transcription factors drive initial Xist upregulation after fertilization through direct activation of long-range enhancers.
  44. A case of mistaken epigenetic identity.
  45. c-Myc uses Cul4b to preserve genome integrity and promote antiviral CD8+ T cell immunity.
  46. Ancestry-specific polygenic risk scores are risk enhancers for clinical cardiovascular disease assessments.
  47. FNIP1 abrogation promotes functional revascularization of ischemic skeletal muscle by driving macrophage recruitment.
  48. Spliceosome component Usp39 contributes to hepatic lipid homeostasis through the regulation of autophagy.
  49. Towards inclusive and sustainable scientific meetings.
  1. Nat Commun. 2023 Nov 06. 14(1): 6943
    Foxp3 orchestrates reorganization of chromatin architecture to establish regulatory T cell identity.
    Zhi Liu, Dong-Sung Lee, Yuqiong Liang, Ye Zheng, Jesse R Dixon.
      Chromatin conformation reorganization is emerging as an important layer of regulation for gene expression and lineage specification. Yet, how lineage-specific transcription factors contribute to the establishment of cell type-specific 3D chromatin architecture in the immune cells remains unclear, especially for the late stages of T cell subset differentiation and maturation. Regulatory T cells (Treg) are mainly generated in the thymus as a subpopulation of T cells specializing in suppressing excessive immune responses. Here, by comprehensively mapping 3D chromatin organization during Treg cell differentiation, we show that Treg-specific chromatin structures were progressively established during its lineage specification, and highly associated with Treg signature gene expression. Additionally, the binding sites of Foxp3, a Treg lineage specifying transcription factor, were highly enriched at Treg-specific chromatin loop anchors. Further comparison of the chromatin interactions between wide-type Tregs versus Treg cells from Foxp3 knock-in/knockout or newly-generated Foxp3 domain-swap mutant mouse revealed that Foxp3 was essential for the establishment of Treg-specific 3D chromatin architecture, although it was not dependent on the formation of the Foxp3 domain-swapped dimer. These results highlighted an underappreciated role of Foxp3 in modulating Treg-specific 3D chromatin structure formation.
    DOI:  https://doi.org/10.1038/s41467-023-42647-y
  2. Nat Immunol. 2023 Nov 06.
    IL-27 gives a good gut feeling about immune regulation.
    Emily R Siniscalco, Joe Craft.
      
    DOI:  https://doi.org/10.1038/s41590-023-01683-y
  3. Nature. 2023 Nov 08.
    Latent human herpesvirus 6 is reactivated in CAR T cells.
    Caleb A Lareau, Yajie Yin, Katie Maurer, Katalin D Sandor, Bence Daniel, Garima Yagnik, José Peña, Jeremy Chase Crawford, Anne M Spanjaart, Jacob C Gutierrez, Nicholas J Haradhvala, Janice M Riberdy, Tsion Abay, Robert R Stickels, Jeffrey M Verboon, Vincent Liu, Frank A Buquicchio, Fangyi Wang, Jackson Southard, Ren Song, Wenjing Li, Aastha Shrestha, Laxmi Parida, Gad Getz, Marcela V Maus, Shuqiang Li, Alison Moore, Zachary J Roberts, Leif S Ludwig, Aimee C Talleur, Paul G Thomas, Houman Dehghani, Thomas Pertel, Anshul Kundaje, Stephen Gottschalk, Theodore L Roth, Marie J Kersten, Catherine J Wu, Robbie G Majzner, Ansuman T Satpathy.
      Cell therapies have yielded durable clinical benefits for patients with cancer, but the risks associated with the development of therapies from manipulated human cells are understudied. For example, we lack a comprehensive understanding of the mechanisms of toxicities observed in patients receiving T cell therapies, including recent reports of encephalitis caused by reactivation of human herpesvirus 6 (HHV-6)1. Here, through petabase-scale viral genomics mining, we examine the landscape of human latent viral reactivation and demonstrate that HHV-6B can become reactivated in cultures of human CD4+ T cells. Using single-cell sequencing, we identify a rare population of HHV-6 'super-expressors' (about 1 in 300-10,000 cells) that possess high viral transcriptional activity, among research-grade allogeneic chimeric antigen receptor (CAR) T cells. By analysing single-cell sequencing data from patients receiving cell therapy products that are approved by the US Food and Drug Administration2 or are in clinical studies3-5, we identify the presence of HHV-6-super-expressor CAR T cells in patients in vivo. Together, the findings of our study demonstrate the utility of comprehensive genomics analyses in implicating cell therapy products as a potential source contributing to the lytic HHV-6 infection that has been reported in clinical trials1,6-8 and may influence the design and production of autologous and allogeneic cell therapies.
    DOI:  https://doi.org/10.1038/s41586-023-06704-2
  4. Nat Commun. 2023 Nov 03. 14(1): 7034
    Integrative analysis reveals a conserved role for the amyloid precursor protein in proteostasis during aging.
    Vanitha Nithianandam, Hassan Bukhari, Matthew J Leventhal, Rachel A Battaglia, Xianjun Dong, Ernest Fraenkel, Mel B Feany.
      Aβ peptides derived from the amyloid precursor protein (APP) have been strongly implicated in the pathogenesis of Alzheimer's disease. However, the normal function of APP and the importance of that role in neurodegenerative disease is less clear. We recover the Drosophila ortholog of APP, Appl, in an unbiased forward genetic screen for neurodegeneration mutants. We perform comprehensive single cell transcriptional and proteomic studies of Appl mutant flies to investigate Appl function in the aging brain. We find an unexpected role for Appl in control of multiple cellular pathways, including translation, mitochondrial function, nucleic acid and lipid metabolism, cellular signaling and proteostasis. We mechanistically define a role for Appl in regulating autophagy through TGFβ signaling and document the broader relevance of our findings using mouse genetic, human iPSC and in vivo tauopathy models. Our results demonstrate a conserved role for APP in controlling age-dependent proteostasis with plausible relevance to Alzheimer's disease.
    DOI:  https://doi.org/10.1038/s41467-023-42822-1
  5. Nat Commun. 2023 Nov 09. 14(1): 7246
    Cryo-electron tomography of NLRP3-activated ASC complexes reveals organelle co-localization.
    Yangci Liu, Haoming Zhai, Helen Alemayehu, Jérôme Boulanger, Lee J Hopkins, Alicia C Borgeaud, Christina Heroven, Jonathan D Howe, Kendra E Leigh, Clare E Bryant, Yorgo Modis.
      NLRP3 induces caspase-1-dependent pyroptotic cell death to drive inflammation. Aberrant activity of NLRP3 occurs in many human diseases. NLRP3 activation induces ASC polymerization into a single, micron-scale perinuclear punctum. Higher resolution imaging of this signaling platform is needed to understand how it induces pyroptosis. Here, we apply correlative cryo-light microscopy and cryo-electron tomography to visualize ASC/caspase-1 in NLRP3-activated cells. The puncta are composed of branched ASC filaments, with a tubular core formed by the pyrin domain. Ribosomes and Golgi-like or endosomal vesicles permeate the filament network, consistent with roles for these organelles in NLRP3 activation. Mitochondria are not associated with ASC but have outer-membrane discontinuities the same size as gasdermin D pores, consistent with our data showing gasdermin D associates with mitochondria and contributes to mitochondrial depolarization.
    DOI:  https://doi.org/10.1038/s41467-023-43180-8
  6. Nat Immunol. 2023 Nov 06.
    Selective IL-27 production by intestinal regulatory T cells permits gut-specific regulation of TH17 cell immunity.
    Chia-Hao Lin, Cheng-Jang Wu, Sunglim Cho, Rasika Patkar, William J Huth, Ling-Li Lin, Mei-Chi Chen, Elisabeth Israelsson, Joanne Betts, Magdalena Niedzielska, Shefali A Patel, Han G Duong, Romana R Gerner, Chia-Yun Hsu, Matthew Catley, Rose A Maciewicz, Hiutung Chu, Manuela Raffatellu, John T Chang, Li-Fan Lu.
      Regulatory T cells (Treg cells) are instrumental in establishing immunological tolerance. However, the precise effector mechanisms by which Treg cells control a specific type of immune response in a given tissue remains unresolved. By simultaneously studying Treg cells from different tissue origins under systemic autoimmunity, in the present study we show that interleukin (IL)-27 is specifically produced by intestinal Treg cells to regulate helper T17 cell (TH17 cell) immunity. Selectively increased intestinal TH17 cell responses in mice with Treg cell-specific IL-27 ablation led to exacerbated intestinal inflammation and colitis-associated cancer, but also helped protect against enteric bacterial infection. Furthermore, single-cell transcriptomic analysis has identified a CD83+CD62Llo Treg cell subset that is distinct from previously characterized intestinal Treg cell populations as the main IL-27 producers. Collectively, our study uncovers a new Treg cell suppression mechanism crucial for controlling a specific type of immune response in a particular tissue and provides further mechanistic insights into tissue-specific Treg cell-mediated immune regulation.
    DOI:  https://doi.org/10.1038/s41590-023-01667-y
  7. Nat Commun. 2023 Nov 07. 14(1): 6947
    Transcriptional reprogramming by mutated IRF4 in lymphoma.
    Nikolai Schleussner, Pierre Cauchy, Vedran Franke, Maciej Giefing, Oriol Fornes, Naveen Vankadari, Salam A Assi, Mariantonia Costanza, Marc A Weniger, Altuna Akalin, Ioannis Anagnostopoulos, Thomas Bukur, Marco G Casarotto, Frederik Damm, Oliver Daumke, Benjamin Edginton-White, J Christof M Gebhardt, Michael Grau, Stephan Grunwald, Martin-Leo Hansmann, Sylvia Hartmann, Lionel Huber, Eva Kärgel, Simone Lusatis, Daniel Noerenberg, Nadine Obier, Ulrich Pannicke, Anja Fischer, Anja Reisser, Andreas Rosenwald, Klaus Schwarz, Srinivasan Sundararaj, Andre Weilemann, Wiebke Winkler, Wendan Xu, Georg Lenz, Klaus Rajewsky, Wyeth W Wasserman, Peter N Cockerill, Claus Scheidereit, Reiner Siebert, Ralf Küppers, Rudolf Grosschedl, Martin Janz, Constanze Bonifer, Stephan Mathas.
      Disease-causing mutations in genes encoding transcription factors (TFs) can affect TF interactions with their cognate DNA-binding motifs. Whether and how TF mutations impact upon the binding to TF composite elements (CE) and the interaction with other TFs is unclear. Here, we report a distinct mechanism of TF alteration in human lymphomas with perturbed B cell identity, in particular classic Hodgkin lymphoma. It is caused by a recurrent somatic missense mutation c.295 T > C (p.Cys99Arg; p.C99R) targeting the center of the DNA-binding domain of Interferon Regulatory Factor 4 (IRF4), a key TF in immune cells. IRF4-C99R fundamentally alters IRF4 DNA-binding, with loss-of-binding to canonical IRF motifs and neomorphic gain-of-binding to canonical and non-canonical IRF CEs. IRF4-C99R thoroughly modifies IRF4 function by blocking IRF4-dependent plasma cell induction, and up-regulates disease-specific genes in a non-canonical Activator Protein-1 (AP-1)-IRF-CE (AICE)-dependent manner. Our data explain how a single mutation causes a complex switch of TF specificity and gene regulation and open the perspective to specifically block the neomorphic DNA-binding activities of a mutant TF.
    DOI:  https://doi.org/10.1038/s41467-023-41954-8
  8. Nat Commun. 2023 Nov 08. 14(1): 7201
    The alarmin IL33 orchestrates type 2 immune-mediated control of thymus regeneration.
    Emilie J Cosway, Kieran D James, Andrea J White, Sonia M Parnell, Andrea Bacon, Andrew N J McKenzie, W E Jenkinson, Graham Anderson.
      As the primary site of T-cell development, the thymus dictates immune competency of the host. The rates of thymus function are not constant, and thymus regeneration is essential to restore new T-cell production following tissue damage from environmental factors and therapeutic interventions. Here, we show the alarmin interleukin (IL) 33 is a product of Sca1+ thymic mesenchyme both necessary and sufficient for thymus regeneration via a type 2 innate immune network. IL33 stimulates expansion of IL5-producing type 2 innate lymphoid cells (ILC2), which triggers a cellular switch in the intrathymic availability of IL4. This enables eosinophil production of IL4 to re-establish thymic mesenchyme prior to recovery of thymopoiesis-inducing epithelial compartments. Collectively, we identify a positive feedback mechanism of type 2 innate immunity that regulates the recovery of thymus function following tissue injury.
    DOI:  https://doi.org/10.1038/s41467-023-43072-x
  9. Nat Rev Immunol. 2023 Nov 03.
    Lipid metabolism extinguishes cGAS-STING-induced inflammation.
    Kirsty Minton.
      
    DOI:  https://doi.org/10.1038/s41577-023-00962-x
  10. Nat Commun. 2023 Nov 04. 14(1): 7081
    Tissue-resident B cells orchestrate macrophage polarisation and function.
    Ondrej Suchanek, John R Ferdinand, Zewen K Tuong, Sathi Wijeyesinghe, Anita Chandra, Ann-Katrin Clauder, Larissa N Almeida, Simon Clare, Katherine Harcourt, Christopher J Ward, Rachael Bashford-Rogers, Trevor Lawley, Rudolf A Manz, Klaus Okkenhaug, David Masopust, Menna R Clatworthy.
      B cells play a central role in humoral immunity but also have antibody-independent functions. Studies to date have focused on B cells in blood and secondary lymphoid organs but whether B cells reside in non-lymphoid organs (NLO) in homeostasis is unknown. Here we identify, using intravenous labeling and parabiosis, a bona-fide tissue-resident B cell population in lung, liver, kidney and urinary bladder, a substantial proportion of which are B-1a cells. Tissue-resident B cells are present in neonatal tissues and also in germ-free mice NLOs, albeit in lower numbers than in specific pathogen-free mice and following co-housing with 'pet-store' mice. They spatially co-localise with macrophages and regulate their polarization and function, promoting an anti-inflammatory phenotype, in-part via interleukin-10 production, with effects on bacterial clearance during urinary tract infection. Thus, our data reveal a critical role for tissue-resident B cells in determining the homeostatic 'inflammatory set-point' of myeloid cells, with important consequences for tissue immunity.
    DOI:  https://doi.org/10.1038/s41467-023-42625-4
  11. Nat Commun. 2023 Nov 04. 14(1): 7086
    Alternative lengthening of telomeres (ALT) cells viability is dependent on C-rich telomeric RNAs.
    Ilaria Rosso, Corey Jones-Weinert, Francesca Rossiello, Matteo Cabrini, Silvia Brambillasca, Leonel Munoz-Sagredo, Zeno Lavagnino, Emanuele Martini, Enzo Tedone, Massimiliano Garre', Julio Aguado, Dario Parazzoli, Marina Mione, Jerry W Shay, Ciro Mercurio, Fabrizio d'Adda di Fagagna.
      Alternative lengthening of telomeres (ALT) is a telomere maintenance mechanism activated in ~10-15% of cancers, characterized by telomeric damage. Telomeric damage-induced long non-coding RNAs (dilncRNAs) are transcribed at dysfunctional telomeres and contribute to telomeric DNA damage response (DDR) activation and repair. Here we observed that telomeric dilncRNAs are preferentially elevated in ALT cells. Inhibition of C-rich (teloC) dilncRNAs with antisense oligonucleotides leads to DNA replication stress responses, increased genomic instability, and apoptosis induction selectively in ALT cells. Cell death is dependent on DNA replication and is increased by DNA replication stress. Mechanistically, teloC dilncRNA inhibition reduces RAD51 and 53BP1 recruitment to telomeres, boosts the engagement of BIR machinery, and increases C-circles and telomeric sister chromatid exchanges, without increasing telomeric non-S phase synthesis. These results indicate that teloC dilncRNA is necessary for a coordinated recruitment of DDR factors to ALT telomeres and it is essential for ALT cancer cells survival.
    DOI:  https://doi.org/10.1038/s41467-023-42831-0
  12. Sci Adv. 2023 Nov 10. 9(45): eadf6251
    Single-cell genomics reveals region-specific developmental trajectories underlying neuronal diversity in the human hypothalamus.
    Brian R Herb, Hannah J Glover, Aparna Bhaduri, Carlo Colantuoni, Tracy L Bale, Kimberly Siletti, Rebecca Hodge, Ed Lein, Arnold R Kriegstein, Claudia A Doege, Seth A Ament.
      The development and diversity of neuronal subtypes in the human hypothalamus has been insufficiently characterized. To address this, we integrated transcriptomic data from 241,096 cells (126,840 newly generated) in the prenatal and adult human hypothalamus to reveal a temporal trajectory from proliferative stem cell populations to mature hypothalamic cell types. Iterative clustering of the adult neurons identified 108 robust transcriptionally distinct neuronal subtypes representing 10 hypothalamic nuclei. Pseudotime trajectories provided insights into the genes driving formation of these nuclei. Comparisons to single-cell transcriptomic data from the mouse hypothalamus suggested extensive conservation of neuronal subtypes despite certain differences in species-enriched gene expression. The uniqueness of hypothalamic neuronal lineages was examined developmentally by comparing excitatory lineages present in cortex and inhibitory lineages in ganglionic eminence, revealing both distinct and shared drivers of neuronal maturation across the human forebrain. These results provide a comprehensive transcriptomic view of human hypothalamus development through gestation and adulthood at cellular resolution.
    DOI:  https://doi.org/10.1126/sciadv.adf6251
  13. Nat Commun. 2023 Nov 04. 14(1): 7102
    Transcriptional repression of beige fat innervation via a YAP/TAZ-S100B axis.
    Xun Huang, Xinmeng Li, Hongyu Shen, Yiheng Zhao, Zhao Zhou, Yushuang Wang, Jingfei Yao, Kaili Xue, Dongmei Wu, Yifu Qiu.
      Sympathetic innervation is essential for the development of functional beige fat that maintains body temperature and metabolic homeostasis, yet the molecular mechanisms controlling this innervation remain largely unknown. Here, we show that adipocyte YAP/TAZ inhibit sympathetic innervation of beige fat by transcriptional repression of neurotropic factor S100B. Adipocyte-specific loss of Yap/Taz induces S100b expression to stimulate sympathetic innervation and biogenesis of functional beige fat both in subcutaneous white adipose tissue (WAT) and browning-resistant visceral WAT. Mechanistically, YAP/TAZ compete with C/EBPβ for binding to the zinc finger-2 domain of PRDM16 to suppress S100b transcription, which is released by adrenergic-stimulated YAP/TAZ phosphorylation and inactivation. Importantly, Yap/Taz loss in adipocytes or AAV-S100B overexpression in visceral WAT restricts both age-associated and diet-induced obesity, and improves metabolic homeostasis by enhancing energy expenditure of mice. Together, our data reveal that YAP/TAZ act as a brake on the beige fat innervation by blocking PRDM16-C/EBPβ-mediated S100b expression.
    DOI:  https://doi.org/10.1038/s41467-023-43021-8
  14. Nat Immunol. 2023 Nov 06.
    A distinct subtype of stromal cell orchestrates the inflammatory response to tissue injury.
      
    DOI:  https://doi.org/10.1038/s41590-023-01670-3
  15. Nat Cell Biol. 2023 Nov;25(11): 1561
    Scarless healing.
    Stylianos Lefkopoulos.
      
    DOI:  https://doi.org/10.1038/s41556-023-01292-9
  16. Cell. 2023 Oct 29. pii: S0092-8674(23)01088-7. [Epub ahead of print]
    Global identification of SWI/SNF targets reveals compensation by EP400.
    Benjamin J E Martin, Eileen F Ablondi, Christine Goglia, Claudia A Mimoso, Piero R Espinel-Cabrera, Karen Adelman.
      Mammalian SWI/SNF chromatin remodeling complexes move and evict nucleosomes at gene promoters and enhancers to modulate DNA access. Although SWI/SNF subunits are commonly mutated in disease, therapeutic options are limited by our inability to predict SWI/SNF gene targets and conflicting studies on functional significance. Here, we leverage a fast-acting inhibitor of SWI/SNF remodeling to elucidate direct targets and effects of SWI/SNF. Blocking SWI/SNF activity causes a rapid and global loss of chromatin accessibility and transcription. Whereas repression persists at most enhancers, we uncover a compensatory role for the EP400/TIP60 remodeler, which reestablishes accessibility at most promoters during prolonged loss of SWI/SNF. Indeed, we observe synthetic lethality between EP400 and SWI/SNF in cancer cell lines and human cancer patient data. Our data define a set of molecular genomic features that accurately predict gene sensitivity to SWI/SNF inhibition in diverse cancer cell lines, thereby improving the therapeutic potential of SWI/SNF inhibitors.
    Keywords:  BRG1; EP400; PRO-seq; RNAPII; SWI/SNF; chromatin accessibility; chromatin remodeling; combination therapies; epigenetic regulators; transcription
    DOI:  https://doi.org/10.1016/j.cell.2023.10.006
  17. Nat Commun. 2023 Nov 08. 14(1): 7207
    Cryo-EM structures of human magnesium channel MRS2 reveal gating and regulatory mechanisms.
    Louis Tung Faat Lai, Jayashree Balaraman, Fei Zhou, Doreen Matthies.
      Magnesium ions (Mg2+) play an essential role in cellular physiology. In mitochondria, protein and ATP synthesis and various metabolic pathways are directly regulated by Mg2+. MRS2, a magnesium channel located in the inner mitochondrial membrane, mediates the influx of Mg2+ into the mitochondrial matrix and regulates Mg2+ homeostasis. Knockdown of MRS2 in human cells leads to reduced uptake of Mg2+ into mitochondria and disruption of the mitochondrial metabolism. Despite the importance of MRS2, the Mg2+ translocation and regulation mechanisms of MRS2 are still unclear. Here, using cryo-EM we report the structures of human MRS2 in the presence and absence of Mg2+ at 2.8 Å and 3.3 Å, respectively. From the homo-pentameric structures, we identify R332 and M336 as major gating residues, which are then tested using mutagenesis and two cellular divalent ion uptake assays. A network of hydrogen bonds is found connecting the gating residue R332 to the soluble domain, potentially regulating the gate. Two Mg2+-binding sites are identified in the MRS2 soluble domain, distinct from the two sites previously reported in CorA, a homolog of MRS2 in prokaryotes. Altogether, this study provides the molecular basis for understanding the Mg2+ translocation and regulatory mechanisms of MRS2.
    DOI:  https://doi.org/10.1038/s41467-023-42599-3
  18. Nat Aging. 2023 Nov 09.
    Spatial and single-cell profiling of the metabolome, transcriptome and epigenome of the aging mouse liver.
    Chrysa Nikopoulou, Niklas Kleinenkuhnen, Swati Parekh, Tonantzi Sandoval, Christoph Ziegenhain, Farina Schneider, Patrick Giavalisco, Kat-Folz Donahue, Anna Juliane Vesting, Marcel Kirchner, Mihaela Bozukova, Christian Vossen, Janine Altmüller, Thomas Wunderlich, Rickard Sandberg, Vangelis Kondylis, Achim Tresch, Peter Tessarz.
      Tissues within an organism and even cell types within a tissue can age with different velocities. However, it is unclear whether cells of one type experience different aging trajectories within a tissue depending on their spatial location. Here, we used spatial transcriptomics in combination with single-cell ATAC-seq and RNA-seq, lipidomics and functional assays to address how cells in the male murine liver are affected by age-related changes in the microenvironment. Integration of the datasets revealed zonation-specific and age-related changes in metabolic states, the epigenome and transcriptome. The epigenome changed in a zonation-dependent manner and functionally, periportal hepatocytes were characterized by decreased mitochondrial fitness, whereas pericentral hepatocytes accumulated large lipid droplets. Together, we provide evidence that changing microenvironments within a tissue exert strong influences on their resident cells that can shape epigenetic, metabolic and phenotypic outputs.
    DOI:  https://doi.org/10.1038/s43587-023-00513-y
  19. Nat Commun. 2023 Nov 08. 14(1): 7200
    Themis2 regulates natural killer cell memory function and formation.
    Tsukasa Nabekura, Elfira Amalia Deborah, Saeko Tahara, Yuya Arai, Paul E Love, Koichiro Kako, Akiyoshi Fukamizu, Masafumi Muratani, Akira Shibuya.
      Immunological memory is a hallmark of the adaptive immune system. Although natural killer (NK) cells are innate immune cells important for the immediate host defence, they can differentiate into memory NK cells. The molecular mechanisms controlling this differentiation are yet to be fully elucidated. Here we identify the scaffold protein Themis2 as a critical regulator of memory NK cell differentiation and function. Themis2-deficient NK cells expressing Ly49H, an activating NK receptor for the mouse cytomegalovirus (MCMV) antigen m157, show enhanced differentiation into memory NK cells and augment host protection against MCMV infection. Themis2 inhibits the effector function of NK cells after stimulation of Ly49H and multiple activating NK receptors, though not specific to memory NK cells. Mechanistically, Themis2 suppresses Ly49H signalling by attenuating ZAP70/Syk phosphorylation, and it also translocates to the nucleus, where it promotes Zfp740-mediated repression to regulate the persistence of memory NK cells. Zfp740 deficiency increases the number of memory NK cells and enhances the effector function of memory NK cells, which further supports the relevance of the Themis2-Zfp740 pathway. In conclusion, our study shows that Themis2 quantitatively and qualitatively regulates NK cell memory formation.
    DOI:  https://doi.org/10.1038/s41467-023-42578-8
  20. Nature. 2023 Nov 10.
    AI that reads brain scans shows promise for finding Alzheimer's genes.
    Max Kozlov.
      
    Keywords:  Genomics; Neuroscience
    DOI:  https://doi.org/10.1038/d41586-023-03482-9
  21. Nat Aging. 2023 Nov 09.
    The CRTC-1 transcriptional domain is required for COMPASS complex-mediated longevity in C. elegans.
    Carlos G Silva-García, Laura I Láscarez-Lagunas, Katharina Papsdorf, Caroline Heintz, Aditi Prabhakar, Christopher S Morrow, Lourdes Pajuelo Torres, Arpit Sharma, Jihe Liu, Monica P Colaiácovo, Anne Brunet, William B Mair.
      Loss of function during aging is accompanied by transcriptional drift, altering gene expression and contributing to a variety of age-related diseases. CREB-regulated transcriptional coactivators (CRTCs) have emerged as key regulators of gene expression that might be targeted to promote longevity. Here we define the role of the Caenorhabditis elegans CRTC-1 in the epigenetic regulation of longevity. Endogenous CRTC-1 binds chromatin factors, including components of the COMPASS complex, which trimethylates lysine 4 on histone H3 (H3K4me3). CRISPR editing of endogenous CRTC-1 reveals that the CREB-binding domain in neurons is specifically required for H3K4me3-dependent longevity. However, this effect is independent of CREB but instead acts via the transcription factor AP-1. Strikingly, CRTC-1 also mediates global histone acetylation levels, and this acetylation is essential for H3K4me3-dependent longevity. Indeed, overexpression of an acetyltransferase enzyme is sufficient to promote longevity in wild-type worms. CRTCs, therefore, link energetics to longevity by critically fine-tuning histone acetylation and methylation to promote healthy aging.
    DOI:  https://doi.org/10.1038/s43587-023-00517-8
  22. Nat Rev Immunol. 2023 Nov 08.
    Bacteria tag tumours for CAR T cell attack.
    M Teresa Villanueva.
      
    DOI:  https://doi.org/10.1038/s41577-023-00971-w
  23. Mol Cell. 2023 Nov 02. pii: S1097-2765(23)00865-1. [Epub ahead of print]
    FMRP phosphorylation modulates neuronal translation through YTHDF1.
    Zhongyu Zou, Jiangbo Wei, Yantao Chen, Yunhee Kang, Hailing Shi, Fan Yang, Zhuoyue Shi, Shijie Chen, Ying Zhou, Caraline Sepich-Poore, Xiaoxi Zhuang, Xiaoming Zhou, Hualiang Jiang, Zhexing Wen, Peng Jin, Cheng Luo, Chuan He.
      RNA-binding proteins (RBPs) control messenger RNA fate in neurons. Here, we report a mechanism that the stimuli-induced neuronal translation is mediated by phosphorylation of a YTHDF1-binding protein FMRP. Mechanistically, YTHDF1 can condense with ribosomal proteins to promote the translation of its mRNA targets. FMRP regulates this process by sequestering YTHDF1 away from the ribosome; upon neuronal stimulation, FMRP becomes phosphorylated and releases YTHDF1 for translation upregulation. We show that a new small molecule inhibitor of YTHDF1 can reverse fragile X syndrome (FXS) developmental defects associated with FMRP deficiency in an organoid model. Our study thus reveals that FMRP and its phosphorylation are important regulators of activity-dependent translation during neuronal development and stimulation and identifies YTHDF1 as a potential therapeutic target for FXS in which developmental defects caused by FMRP depletion could be reversed through YTHDF1 inhibition.
    Keywords:  FMRP; RNA-binding proteins; YTHDF1; m(6)A; neuronal translation control; protein condensates
    DOI:  https://doi.org/10.1016/j.molcel.2023.10.028
  24. Nat Commun. 2023 Nov 09. 14(1): 7239
    Structures of the DarR transcription regulator reveal unique modes of second messenger and DNA binding.
    Maria A Schumacher, Nicholas Lent, Vincent B Chen, Raul Salinas.
      The mycobacterial repressor, DarR, a TetR family regulator (TFR), was the first transcription regulator shown to bind c-di-AMP. However, the molecular basis for this interaction and the mechanism involved in DNA binding by DarR remain unknown. Here we describe DarR-c-di-AMP and DarR-DNA structures and complementary biochemical assays. The DarR-c-di-AMP structure reveals a unique effector binding site for a TFR, located between DarR dimer subunits. Strikingly, we show this motif also binds cAMP. The location of the adenine nucleotide binding site between subunits suggests this interaction may facilitate dimerization and hence DNA binding. Indeed, biochemical assays show cAMP enhances DarR DNA binding. Finally, DarR-DNA structures reveal a distinct TFR DNA-binding mechanism involving two interacting dimers on the DNA. Thus, the combined data unveil a newly described second messenger binding motif and DNA binding mode for this important family of regulators.
    DOI:  https://doi.org/10.1038/s41467-023-42823-0
  25. Nature. 2023 Nov 08.
    Deconstruction of rheumatoid arthritis synovium defines inflammatory subtypes.
    Accelerating Medicines Partnership: RA/SLE Network
      Rheumatoid arthritis is a prototypical autoimmune disease that causes joint inflammation and destruction1. There is currently no cure for rheumatoid arthritis, and the effectiveness of treatments varies across patients, suggesting an undefined pathogenic diversity1,2. Here, to deconstruct the cell states and pathways that characterize this pathogenic heterogeneity, we profiled the full spectrum of cells in inflamed synovium from patients with rheumatoid arthritis. We used multi-modal single-cell RNA-sequencing and surface protein data coupled with histology of synovial tissue from 79 donors to build single-cell atlas of rheumatoid arthritis synovial tissue that includes more than 314,000 cells. We stratified tissues into six groups, referred to as cell-type abundance phenotypes (CTAPs), each characterized by selectively enriched cell states. These CTAPs demonstrate the diversity of synovial inflammation in rheumatoid arthritis, ranging from samples enriched for T and B cells to those largely lacking lymphocytes. Disease-relevant cell states, cytokines, risk genes, histology and serology metrics are associated with particular CTAPs. CTAPs are dynamic and can predict treatment response, highlighting the clinical utility of classifying rheumatoid arthritis synovial phenotypes. This comprehensive atlas and molecular, tissue-based stratification of rheumatoid arthritis synovial tissue reveal new insights into rheumatoid arthritis pathology and heterogeneity that could inform novel targeted treatments.
    DOI:  https://doi.org/10.1038/s41586-023-06708-y
  26. Nat Commun. 2023 Nov 09. 14(1): 7254
    Functional alterations of the prefrontal circuit underlying cognitive aging in mice.
    Huee Ru Chong, Yadollah Ranjbar-Slamloo, Malcolm Zheng Hao Ho, Xuan Ouyang, Tsukasa Kamigaki.
      Executive function is susceptible to aging. How aging impacts the circuit-level computations underlying executive function remains unclear. Using calcium imaging and optogenetic manipulation during memory-guided behavior, we show that working-memory coding and the relevant recurrent connectivity in the mouse medial prefrontal cortex (mPFC) are altered as early as middle age. Population activity in the young adult mPFC exhibits dissociable yet overlapping patterns between tactile and auditory modalities, enabling crossmodal memory coding concurrent with modality-dependent coding. In middle age, however, crossmodal coding remarkably diminishes while modality-dependent coding persists, and both types of coding decay in advanced age. Resting-state functional connectivity, especially among memory-coding neurons, decreases already in middle age, suggesting deteriorated recurrent circuits for memory maintenance. Optogenetic inactivation reveals that the middle-aged mPFC exhibits heightened vulnerability to perturbations. These findings elucidate functional alterations of the prefrontal circuit that unfold in middle age and deteriorate further as a hallmark of cognitive aging.
    DOI:  https://doi.org/10.1038/s41467-023-43142-0
  27. Nat Cell Biol. 2023 Nov;25(11): 1561
    Condensing to target RNAs.
    Daryl J V David.
      
    DOI:  https://doi.org/10.1038/s41556-023-01293-8
  28. Nat Commun. 2023 Nov 09. 14(1): 7236
    Spatial-linked alignment tool (SLAT) for aligning heterogenous slices.
    Chen-Rui Xia, Zhi-Jie Cao, Xin-Ming Tu, Ge Gao.
      Spatially resolved omics technologies reveal the spatial organization of cells in various biological systems. Here we propose SLAT (Spatially-Linked Alignment Tool), a graph-based algorithm for efficient and effective alignment of spatial slices. Adopting a graph adversarial matching strategy, SLAT is the first algorithm capable of aligning heterogenous spatial data across distinct technologies and modalities. Systematic benchmarks demonstrate SLAT's superior precision, robustness, and speed over existing state-of-the-arts. Applications to multiple real-world datasets further show SLAT's utility in enhancing cell-typing resolution, integrating multiple modalities for regulatory inference, and mapping fine-scale spatial-temporal changes during development. The full SLAT package is available at https://github.com/gao-lab/SLAT .
    DOI:  https://doi.org/10.1038/s41467-023-43105-5
  29. Proc Natl Acad Sci U S A. 2023 Nov 14. 120(46): e2312810120
    Essential requirement for IER3IP1 in B cell development.
    Xue Zhong, James J Moresco, Katie Keller, Danielle Renee Lazaro, Claire Ely, Eva Marie Y Moresco, Bruce Beutler, Jin Huk Choi.
      In a forward genetic screen of mice with N-ethyl-N-nitrosourea-induced mutations for aberrant immune function, we identified animals with low percentages of B220+ cells in the peripheral blood. The causative mutation was in Ier3ip1, encoding immediate early response 3 interacting protein 1 (IER3IP1), an endoplasmic reticulum membrane protein mutated in an autosomal recessive neurodevelopmental disorder termed Microcephaly with simplified gyration, Epilepsy and permanent neonatal Diabetes Syndrome (MEDS) in humans. However, no immune function for IER3IP1 had previously been reported. The viable hypomorphic Ier3ip1 allele uncovered in this study, identical to a reported IER3IP1 variant in a MEDS patient, reveals an essential hematopoietic-intrinsic role for IER3IP1 in B cell development and function. We show that IER3IP1 forms a complex with the Golgi transmembrane protein 167A and limits activation of the unfolded protein response mediated by inositol-requiring enzyme-1α and X-box binding protein 1 in B cells. Our findings suggest that B cell deficiency may be a feature of MEDS.
    Keywords:  B cells; ENU; IER3IP1; TMEM167A; unfolded protein response
    DOI:  https://doi.org/10.1073/pnas.2312810120
  30. J Immunol. 2023 Nov 10. pii: ji2300248. [Epub ahead of print]
    SIKs Regulate HDAC7 Stabilization and Cytokine Recall in Late-Stage T Cell Effector Differentiation.
    Rachel S Helms, Alberto Marin-Gonzalez, Chirag H Patel, Im-Hong Sun, Jiayu Wen, Robert D Leone, Bridget Duvall, Run-Duo Gao, Taekjip Ha, Takashi Tsukamoto, Barbara S Slusher, Joel L Pomerantz, Jonathan D Powell.
      Understanding the mechanisms underlying the acquisition and maintenance of effector function during T cell differentiation is important to unraveling how these processes can be dysregulated in the context of disease and manipulated for therapeutic intervention. In this study, we report the identification of a previously unappreciated regulator of murine T cell differentiation through the evaluation of a previously unreported activity of the kinase inhibitor, BioE-1197. Specifically, we demonstrate that liver kinase B1 (LKB1)-mediated activation of salt-inducible kinases epigenetically regulates cytokine recall potential in effector CD8+ and Th1 cells. Evaluation of this phenotype revealed that salt-inducible kinase-mediated phosphorylation-dependent stabilization of histone deacetylase 7 (HDAC7) occurred during late-stage effector differentiation. HDAC7 stabilization increased nuclear HDAC7 levels, which correlated with total and cytokine loci-specific reductions in the activating transcription mark histone 3 lysine 27 acetylation (H3K27Ac). Accordingly, HDAC7 stabilization diminished transcriptional induction of cytokine genes upon restimulation. Inhibition of this pathway during differentiation produced effector T cells epigenetically poised for enhanced cytokine recall. This work identifies a previously unrecognized target for enhancing effector T cell functionality.
    DOI:  https://doi.org/10.4049/jimmunol.2300248
  31. Nat Cell Biol. 2023 Nov;25(11): 1564-1565
    Sperm bud mitochondria to adjust the numbers.
    Diane C Shakes.
      
    DOI:  https://doi.org/10.1038/s41556-023-01255-0
  32. Nat Commun. 2023 Nov 04. 14(1): 7075
    Cell volume controlled by LRRC8A-formed volume-regulated anion channels fine-tunes T cell activation and function.
    Yuman Wang, Zaiqiao Sun, Jieming Ping, Jianlong Tang, Boxiao He, Teding Chang, Qian Zhou, Shijie Yuan, Zhaohui Tang, Xin Li, Yan Lu, Ran He, Ximiao He, Zheng Liu, Lei Yin, Ning Wu.
      Biosynthesis drives the cell volume increase during T cell activation. However, the contribution of cell volume regulation in TCR signaling during T lymphoblast formation and its underlying mechanisms remain unclear. Here we show that cell volume regulation is required for optimal T cell activation. Inhibition of VRACs (volume-regulated anion channels) and deletion of leucine-rich repeat-containing protein 8A (LRRC8A) channel components impair T cell activation and function, particularly under weak TCR stimulation. Additionally, LRRC8A has distinct influences on mRNA transcriptional profiles, indicating the prominent effects of cell volume regulation for T cell functions. Moreover, cell volume regulation via LRRC8A controls T cell-mediated antiviral immunity and shapes the TCR repertoire in the thymus. Mechanistically, LRRC8A governs stringent cell volume increase via regulated volume decrease (RVD) during T cell blast formation to keep the TCR signaling molecules at an adequate density. Together, our results show a further layer of T cell activation regulation that LRRC8A functions as a cell volume controlling "valve" to facilitate T cell activation.
    DOI:  https://doi.org/10.1038/s41467-023-42817-y
  33. Nat Commun. 2023 Nov 04. 14(1): 7107
    A combined adjuvant approach primes robust germinal center responses and humoral immunity in non-human primates.
    Ivy Phung, Kristen A Rodrigues, Ester Marina-Zárate, Laura Maiorino, Bapi Pahar, Wen-Hsin Lee, Mariane Melo, Amitinder Kaur, Carolina Allers, Marissa Fahlberg, Brooke F Grasperge, Jason P Dufour, Faith Schiro, Pyone P Aye, Paul G Lopez, Jonathan L Torres, Gabriel Ozorowski, Saman Eskandarzadeh, Michael Kubitz, Erik Georgeson, Bettina Groschel, Rebecca Nedellec, Michael Bick, Katarzyna Kaczmarek Michaels, Hongmei Gao, Xiaoying Shen, Diane G Carnathan, Guido Silvestri, David C Montefiori, Andrew B Ward, Lars Hangartner, Ronald S Veazey, Dennis R Burton, William R Schief, Darrell J Irvine, Shane Crotty.
      Adjuvants and antigen delivery kinetics can profoundly influence B cell responses and should be critically considered in rational vaccine design, particularly for difficult neutralizing antibody targets such as human immunodeficiency virus (HIV). Antigen kinetics can change depending on the delivery method. To promote extended immunogen bioavailability and to present antigen in a multivalent form, native-HIV Env trimers are modified with short phosphoserine peptide linkers that promote tight binding to aluminum hydroxide (pSer:alum). Here we explore the use of a combined adjuvant approach that incorporates pSer:alum-mediated antigen delivery with potent adjuvants (SMNP, 3M-052) in an extensive head-to-head comparison study with conventional alum to assess germinal center (GC) and humoral immune responses. Priming with pSer:alum plus SMNP induces additive effects that enhance the magnitude and persistence of GCs, which correlate with better GC-TFH cell help. Autologous HIV-neutralizing antibody titers are improved in SMNP-immunized animals after two immunizations. Over 9 months after priming immunization of pSer:alum with either SMNP or 3M-052, robust Env-specific bone marrow plasma cells (BM BPC) are observed. Furthermore, pSer-modification of Env trimer reduce targeting towards immunodominant non-neutralizing epitopes. The study shows that a combined adjuvant approach can augment humoral immunity by modulating immunodominance and shows promise for clinical translation.
    DOI:  https://doi.org/10.1038/s41467-023-42923-x
  34. Nat Aging. 2023 Nov 09.
    A method to identify regulators of senolysis.
    Anna Kriebs.
      
    DOI:  https://doi.org/10.1038/s43587-023-00529-4
  35. Immunity. 2023 Oct 31. pii: S1074-7613(23)00444-2. [Epub ahead of print]
    Gasdermin D permeabilization of mitochondrial inner and outer membranes accelerates and enhances pyroptosis.
    Rui Miao, Cong Jiang, Winston Y Chang, Haiwei Zhang, Jinsu An, Felicia Ho, Pengcheng Chen, Han Zhang, Caroline Junqueira, Dulguun Amgalan, Felix G Liang, Junbing Zhang, Charles L Evavold, Iva Hafner-Bratkovič, Zhibin Zhang, Pietro Fontana, Shiyu Xia, Markus Waldeck-Weiermair, Youdong Pan, Thomas Michel, Liron Bar-Peled, Hao Wu, Jonathan C Kagan, Richard N Kitsis, Peng Zhang, Xing Liu, Judy Lieberman.
      Gasdermin D (GSDMD)-activated inflammatory cell death (pyroptosis) causes mitochondrial damage, but its underlying mechanism and functional consequences are largely unknown. Here, we show that the N-terminal pore-forming GSDMD fragment (GSDMD-NT) rapidly damaged both inner and outer mitochondrial membranes (OMMs) leading to reduced mitochondrial numbers, mitophagy, ROS, loss of transmembrane potential, attenuated oxidative phosphorylation (OXPHOS), and release of mitochondrial proteins and DNA from the matrix and intermembrane space. Mitochondrial damage occurred as soon as GSDMD was cleaved prior to plasma membrane damage. Mitochondrial damage was independent of the B-cell lymphoma 2 family and depended on GSDMD-NT binding to cardiolipin. Canonical and noncanonical inflammasome activation of mitochondrial damage, pyroptosis, and inflammatory cytokine release were suppressed by genetic ablation of cardiolipin synthase (Crls1) or the scramblase (Plscr3) that transfers cardiolipin to the OMM. Phospholipid scramblase-3 (PLSCR3) deficiency in a tumor compromised pyroptosis-triggered anti-tumor immunity. Thus, mitochondrial damage plays a critical role in pyroptosis.
    Keywords:  CRLS1; GSDMD; IL-1; PLSCR3; cardiolipin; mitochondria; pyroptosis
    DOI:  https://doi.org/10.1016/j.immuni.2023.10.004
  36. Sci Adv. 2023 11 10. 9(45): eadm8238
    Editorial expression of concern.
    H Holden Thorp.
      
    DOI:  https://doi.org/10.1126/sciadv.adm8238
  37. Nat Commun. 2023 Nov 03. 14(1): 7060
    Lipofuscin-like autofluorescence within microglia and its impact on studying microglial engulfment.
    Jacob M Stillman, Francisco Mendes Lopes, Jing-Ping Lin, Kevin Hu, Daniel S Reich, Dorothy P Schafer.
      Engulfment of cellular material and proteins is a key function for microglia, a resident macrophage of the central nervous system (CNS). Among the techniques used to measure microglial engulfment, confocal light microscopy has been used the most extensively. Here, we show that autofluorescence (AF) likely due to lipofuscin (lipo-AF) and typically associated with aging, can also be detected within microglial lysosomes in the young mouse brain by light microscopy. This lipo-AF signal accumulates first within microglia and it occurs earliest in white versus gray matter. Importantly, in gray matter, lipo-AF signal can confound the interpretation of antibody-labeled synaptic material within microglia in young adult mice. We further show that there is an age-dependent accumulation of lipo-AF inside and outside of microglia, which is not affected by amyloid plaques. We finally implement a robust and cost-effective strategy to quench AF in mouse, marmoset, and human brain tissue.
    DOI:  https://doi.org/10.1038/s41467-023-42809-y
  38. Nat Cell Biol. 2023 Nov;25(11): 1625-1636
    Mitopherogenesis, a form of mitochondria-specific ectocytosis, regulates sperm mitochondrial quantity and fertility.
    Peng Liu, Jing Shi, Danli Sheng, Wenqing Lu, Jie Guo, Lei Gao, Xiaoqing Wang, Shaofeng Wu, Yanwen Feng, Dashan Dong, Xiaoshuai Huang, Hongyun Tang.
      Mitochondrial export into the extracellular space is emerging as a fundamental cellular process implicated in diverse physiological activities. Although a few studies have shed light on the process of discarding damaged mitochondria, how mitochondria are exported and the functions of mitochondrial release remain largely unclear. Here we describe mitopherogenesis, a formerly unknown process that specifically secretes mitochondria through a unique extracellular vesicle termed a 'mitopher'. We observed that during sperm development in male Caenorhabditis elegans, healthy mitochondria are exported out of the spermatids through mitopherogenesis and each of the generated mitophers harbours only one mitochondrion. In mitopherogenesis, the plasma membrane first forms mitochondrion-embedding outward buds, which then promptly bud off and thereby result in the generation of mitophers. Mechanistically, extracellular protease signalling in the testis triggers mitopher formation from spermatids, which is partially mediated by the tyrosine kinase SPE-8. Moreover, mitopherogenesis requires normal microfilament dynamics, whereas myosin VI antagonizes mitopher generation. Strikingly, our three-dimensional electron microscopy analyses indicate that mitochondrial quantity requires precise modulation during sperm development, which is critically mediated by mitopherogenesis. Inhibition of mitopherogenesis causes accumulation of mitochondria in sperm, which may lead to sperm motility and fertility defects. Our findings identify mitopherogenesis as a previously undescribed process for mitochondria-specific ectocytosis, which may represent a fundamental branch of mechanisms underlying mitochondrial quantity control to regulate cell functions during development.
    DOI:  https://doi.org/10.1038/s41556-023-01264-z
  39. Nat Commun. 2023 Nov 03. 14(1): 7066
    DNAJB6 mutants display toxic gain of function through unregulated interaction with Hsp70 chaperones.
    Meital Abayev-Avraham, Yehuda Salzberg, Dar Gliksberg, Meital Oren-Suissa, Rina Rosenzweig.
      Molecular chaperones are essential cellular components that aid in protein folding and preventing the abnormal aggregation of disease-associated proteins. Mutations in one such chaperone, DNAJB6, were identified in patients with LGMDD1, a dominant autosomal disorder characterized by myofibrillar degeneration and accumulations of aggregated protein within myocytes. The molecular mechanisms through which such mutations cause this dysfunction, however, are not well understood. Here we employ a combination of solution NMR and biochemical assays to investigate the structural and functional changes in LGMDD1 mutants of DNAJB6. Surprisingly, we find that DNAJB6 disease mutants show no reduction in their aggregation-prevention activity in vitro, and instead differ structurally from the WT protein, affecting their interaction with Hsp70 chaperones. While WT DNAJB6 contains a helical element regulating its ability to bind and activate Hsp70, in LGMDD1 disease mutants this regulation is disrupted. These variants can thus recruit and hyperactivate Hsp70 chaperones in an unregulated manner, depleting Hsp70 levels in myocytes, and resulting in the disruption of proteostasis. Interfering with DNAJB6-Hsp70 binding, however, reverses the disease phenotype, suggesting future therapeutic avenues for LGMDD1.
    DOI:  https://doi.org/10.1038/s41467-023-42735-z
  40. Nat Commun. 2023 Nov 04. 14(1): 7090
    Systemic and intrinsic functions of ATRX in glial cell fate and CNS myelination in male mice.
    Megan E Rowland, Yan Jiang, Sarfraz Shafiq, Alireza Ghahramani, Miguel A Pena-Ortiz, Vanessa Dumeaux, Nathalie G Bérubé.
      Myelin, an extension of the oligodendrocyte plasma membrane, wraps around axons to facilitate nerve conduction. Myelination is compromised in ATR-X intellectual disability syndrome patients, but the causes are unknown. We show that loss of ATRX leads to myelination deficits in male mice that are partially rectified upon systemic thyroxine administration. Targeted ATRX inactivation in either neurons or oligodendrocyte progenitor cells (OPCs) reveals OPC-intrinsic effects on myelination. OPCs lacking ATRX fail to differentiate along the oligodendrocyte lineage and acquire a more plastic state that favors astrocytic differentiation in vitro and in vivo. ATRX chromatin occupancy in OPCs greatly overlaps with that of the chromatin remodelers CHD7 and CHD8 as well as H3K27Ac, a mark of active enhancers. Overall, our data indicate that ATRX regulates the onset of myelination systemically via thyroxine, and by promoting OPC differentiation and suppressing astrogliogenesis. These functions of ATRX identified in mice could explain white matter pathogenesis observed in ATR-X syndrome patients.
    DOI:  https://doi.org/10.1038/s41467-023-42752-y
  41. Sci Immunol. 2023 Nov 10. 8(89): eadi9066
    Zfp281 and Zfp148 control CD4+ T cell thymic development and TH2 functions.
    Laura B Chopp, Xiaoliang Zhu, Yayi Gao, Jia Nie, Jatinder Singh, Parimal Kumar, Kelly Z Young, Shil Patel, Caiyi Li, Mariah Balmaceno-Criss, Melanie S Vacchio, Michael M Wang, Ferenc Livak, Juanita L Merchant, Lie Wang, Michael C Kelly, Jinfang Zhu, Rémy Bosselut.
      How CD4+ lineage gene expression is initiated in differentiating thymocytes remains poorly understood. Here, we show that the paralog transcription factors Zfp281 and Zfp148 control both this process and cytokine expression by T helper cell type 2 (TH2) effector cells. Genetic, single-cell, and spatial transcriptomic analyses showed that these factors promote the intrathymic CD4+ T cell differentiation of class II major histocompatibility complex (MHC II)-restricted thymocytes, including expression of the CD4+ lineage-committing factor Thpok. In peripheral T cells, Zfp281 and Zfp148 promoted chromatin opening at and expression of TH2 cytokine genes but not of the TH2 lineage-determining transcription factor Gata3. We found that Zfp281 interacts with Gata3 and is recruited to Gata3 genomic binding sites at loci encoding Thpok and TH2 cytokines. Thus, Zfp148 and Zfp281 collaborate with Gata3 to promote CD4+ T cell development and TH2 cell responses.
    DOI:  https://doi.org/10.1126/sciimmunol.adi9066
  42. Nat Immunol. 2023 Nov 09.
    Regulatory T cell-derived IL-1Ra suppresses the innate response to respiratory viral infection.
    Jason W Griffith, Lucas D Faustino, Victoria I Cottrell, Keshav Nepal, Lida P Hariri, Rebecca Suet-Yan Chiu, Michael C Jones, Amélie Julé, Cem Gabay, Andrew D Luster.
      Regulatory T (Treg) cell modulation of adaptive immunity and tissue homeostasis is well described; however, less is known about Treg cell-mediated regulation of the innate immune response. Here we show that deletion of ST2, the receptor for interleukin (IL)-33, on Treg cells increased granulocyte influx into the lung and increased cytokine production by innate lymphoid and γδ T cells without alteration of adaptive immunity to influenza. IL-33 induced high levels of the interleukin-1 receptor antagonist (IL-1Ra) in ST2+ Treg cells and deletion of IL-1Ra in Treg cells increased granulocyte influx into the lung. Treg cell-specific deletion of ST2 or IL-1Ra improved survival to influenza, which was dependent on IL-1. Adventitial fibroblasts in the lung expressed high levels of the IL-1 receptor and their chemokine production was suppressed by Treg cell-produced IL-1Ra. Thus, we define a new pathway where IL-33-induced IL-1Ra production by tissue Treg cells suppresses IL-1-mediated innate immune responses to respiratory viral infection.
    DOI:  https://doi.org/10.1038/s41590-023-01655-2
  43. Nat Cell Biol. 2023 Nov;25(11): 1704-1715
    GATA transcription factors drive initial Xist upregulation after fertilization through direct activation of long-range enhancers.
    Liat Ravid Lustig, Abhishek Sampath Kumar, Till Schwämmle, Ilona Dunkel, Gemma Noviello, Elodie Limberg, Raha Weigert, Guido Pacini, René Buschow, Afrah Ghauri, Maximilian Stötzel, Lars Wittler, Alexander Meissner, Edda G Schulz.
      X-chromosome inactivation (XCI) balances gene expression between the sexes in female mammals. Shortly after fertilization, upregulation of Xist RNA from one X chromosome initiates XCI, leading to chromosome-wide gene silencing. XCI is maintained in all cell types, except the germ line and the pluripotent state where XCI is reversed. The mechanisms triggering Xist upregulation have remained elusive. Here we identify GATA transcription factors as potent activators of Xist. Through a pooled CRISPR activation screen in murine embryonic stem cells, we demonstrate that GATA1, as well as other GATA transcription factors can drive ectopic Xist expression. Moreover, we describe GATA-responsive regulatory elements in the Xist locus bound by different GATA factors. Finally, we show that GATA factors are essential for XCI induction in mouse preimplantation embryos. Deletion of GATA1/4/6 or GATA-responsive Xist enhancers in mouse zygotes effectively prevents Xist upregulation. We propose that the activity or complete absence of various GATA family members controls initial Xist upregulation, XCI maintenance in extra-embryonic lineages and XCI reversal in the epiblast.
    DOI:  https://doi.org/10.1038/s41556-023-01266-x
  44. Science. 2023 Nov 10. 382(6671): 643-644
    A case of mistaken epigenetic identity.
    Mia T Levine.
      The specialized packaging of sperm DNA preserves genome stability in the fruit fly zygote.
    DOI:  https://doi.org/10.1126/science.adl0365
  45. Nat Commun. 2023 Nov 04. 14(1): 7098
    c-Myc uses Cul4b to preserve genome integrity and promote antiviral CD8+ T cell immunity.
    Asif A Dar, Dale D Kim, Scott M Gordon, Kathleen Klinzing, Siera Rosen, Ipsita Guha, Nadia Porter, Yohaniz Ortega, Katherine S Forsyth, Jennifer Roof, Hossein Fazelinia, Lynn A Spruce, Laurence C Eisenlohr, Edward M Behrens, Paula M Oliver.
      During infection, virus-specific CD8+ T cells undergo rapid bursts of proliferation and differentiate into effector cells that kill virus-infected cells and reduce viral load. This rapid clonal expansion can put T cells at significant risk for replication-induced DNA damage. Here, we find that c-Myc links CD8+ T cell expansion to DNA damage response pathways though the E3 ubiquitin ligase, Cullin 4b (Cul4b). Following activation, c-Myc increases the levels of Cul4b and other members of the Cullin RING Ligase 4 (CRL4) complex. Despite expressing c-Myc at high levels, Cul4b-deficient CD8+ T cells do not expand and clear the Armstrong strain of lymphocytic choriomeningitis virus (LCMV) in vivo. Cul4b-deficient CD8+ T cells accrue DNA damage and succumb to proliferative catastrophe early after antigen encounter. Mechanistically, Cul4b knockout induces an accumulation of p21 and Cyclin E2, resulting in replication stress. Our data show that c-Myc supports cell proliferation by maintaining genome stability via Cul4b, thereby directly coupling these two interdependent pathways. These data clarify how CD8+ T cells use c-Myc and Cul4b to sustain their potential for extraordinary population expansion, longevity and antiviral responses.
    DOI:  https://doi.org/10.1038/s41467-023-42765-7
  46. Nat Commun. 2023 Nov 04. 14(1): 7105
    Ancestry-specific polygenic risk scores are risk enhancers for clinical cardiovascular disease assessments.
    George B Busby, Scott Kulm, Alessandro Bolli, Jen Kintzle, Paolo Di Domenico, Giordano Bottà.
      Clinical implementation of new prediction models requires evaluation of their utility in a broad range of intended use populations. Here we develop and validate ancestry-specific Polygenic Risk Scores (PRSs) for Coronary Artery Disease (CAD) using 29,389 individuals from diverse cohorts and genetic ancestry groups. The CAD PRSs outperform published scores with an average Odds Ratio per Standard Deviation of 1.57 (SD = 0.14) and identify between 12% and 24% of individuals with high genetic risk. Using this risk factor to reclassify borderline or intermediate 10 year Atherosclerotic Cardiovascular Disease (ASCVD) risk improves assessments for both CAD (Net Reclassification Improvement (NRI) = 13.14% (95% CI 9.23-17.06%)) and ASCVD (NRI = 10.70 (95% CI 7.35-14.05)) in an independent cohort of 9,691 individuals. Our analyses demonstrate that using PRSs as Risk Enhancers improves ASCVD risk assessments outlining an approach for guiding ASCVD prevention with genetic information.
    DOI:  https://doi.org/10.1038/s41467-023-42897-w
  47. Nat Commun. 2023 Nov 06. 14(1): 7136
    FNIP1 abrogation promotes functional revascularization of ischemic skeletal muscle by driving macrophage recruitment.
    Zongchao Sun, Likun Yang, Abdukahar Kiram, Jing Yang, Zhuangzhuang Yang, Liwei Xiao, Yujing Yin, Jing Liu, Yan Mao, Danxia Zhou, Hao Yu, Zheng Zhou, Dengqiu Xu, Yuhuan Jia, Chenyun Ding, Qiqi Guo, Hongwei Wang, Yan Li, Li Wang, Tingting Fu, Shijun Hu, Zhenji Gan.
      Ischaemia of the heart and limbs attributable to compromised blood supply is a major cause of mortality and morbidity. The mechanisms of functional angiogenesis remain poorly understood, however. Here we show that FNIP1 plays a critical role in controlling skeletal muscle functional angiogenesis, a process pivotal for muscle revascularization during ischemia. Muscle FNIP1 expression is down-regulated by exercise. Genetic overexpression of FNIP1 in myofiber causes limited angiogenesis in mice, whereas its myofiber-specific ablation markedly promotes the formation of functional blood vessels. Interestingly, the increased muscle angiogenesis is independent of AMPK but due to enhanced macrophage recruitment in FNIP1-depleted muscles. Mechanistically, myofiber FNIP1 deficiency induces PGC-1α to activate chemokine gene transcription, thereby driving macrophage recruitment and muscle angiogenesis program. Furthermore, in a mouse hindlimb ischemia model of peripheral artery disease, the loss of myofiber FNIP1 significantly improved the recovery of blood flow. Thus, these results reveal a pivotal role of FNIP1 as a negative regulator of functional angiogenesis in muscle, offering insight into potential therapeutic strategies for ischemic diseases.
    DOI:  https://doi.org/10.1038/s41467-023-42690-9
  48. Nat Commun. 2023 Nov 03. 14(1): 7032
    Spliceosome component Usp39 contributes to hepatic lipid homeostasis through the regulation of autophagy.
    Donghai Cui, Zixiang Wang, Qianli Dang, Jing Wang, Junchao Qin, Jianping Song, Xiangyu Zhai, Yachao Zhou, Ling Zhao, Gang Lu, Hongbin Liu, Gang Liu, Runping Liu, Changshun Shao, Xiyu Zhang, Zhaojian Liu.
      Regulation of alternative splicing (AS) enables a single transcript to yield multiple isoforms that increase transcriptome and proteome diversity. Here, we report that spliceosome component Usp39 plays a role in the regulation of hepatocyte lipid homeostasis. We demonstrate that Usp39 expression is downregulated in hepatic tissues of non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) subjects. Hepatocyte-specific Usp39 deletion in mice leads to increased lipid accumulation, spontaneous steatosis and impaired autophagy. Combined analysis of RNA immunoprecipitation (RIP-seq) and bulk RNA sequencing (RNA-seq) data reveals that Usp39 regulates AS of several autophagy-related genes. In particular, deletion of Usp39 results in alternative 5' splice site selection of exon 6 in Heat shock transcription factor 1 (Hsf1) and consequently its reduced expression. Importantly, overexpression of Hsf1 could attenuate lipid accumulation caused by Usp39 deficiency. Taken together, our findings indicate that Usp39-mediated AS is required for sustaining autophagy and lipid homeostasis in the liver.
    DOI:  https://doi.org/10.1038/s41467-023-42461-6
  49. Nat Cell Biol. 2023 Nov;25(11): 1557-1560
    Towards inclusive and sustainable scientific meetings.
    Silke Blair Chalmers, Suzanne Madgwick, Bethan Lloyd-Lewis, Urszula Lucja McClurg, Salah Elias, Peter Andersen, Ralitsa Madsen, Vaishnavi Ananthanarayanan, Felicity Mae Davis.
      
    DOI:  https://doi.org/10.1038/s41556-023-01222-9
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