bims-nimamd Biomed News
on Neuroimmunity and neuroinflammation in ageing and metabolic disease
Issue of 2024‒01‒07
63 papers selected by
Fawaz Alzaïd, Sorbonne Université
  1. The glue that holds us together.
  2. A good-for-something second brain.
  3. Nature Communications from the point of view of our very first authors.
  4. Immune imprinting.
  5. The call of activism.
  6. Fructose sweetens antitumor responses.
  7. Epigenetic checkpoints regulate the fate and function of CAR-T cells.
  8. A type 1 immunity-restricted promoter of the IL-33 receptor gene directs antiviral T-cell responses.
  9. Type 1 or type 2 lineage-specific promoters regulate expression of the IL-33 receptor in T cells.
  10. CD4+ T cell immunity is dependent on an intrinsic stem-like program.
  11. TMEM55B links autophagy flux, lysosomal repair, and TFE3 activation in response to oxidative stress.
  12. Vitamin B12 produced by gut bacteria modulates cholinergic signalling.
  13. Ancient DNA reveals evolutionary origins of autoimmune diseases.
  14. From lab to life: how wearable devices can improve health equity.
  15. Feeding the future global population.
  16. Direct translation of incoming retroviral genomes.
  17. Repression of latent NF-κB enhancers by PDX1 regulates β cell functional heterogeneity.
  18. Cell-type differential targeting of SETDB1 prevents aberrant CTCF binding, chromatin looping, and cis-regulatory interactions.
  19. Myeloid-derived grancalcin instigates obesity-induced insulin resistance and metabolic inflammation in male mice.
  20. Cullin5 drives experimental asthma exacerbations by modulating alveolar macrophage antiviral immunity.
  21. Cell cycle arrest induces lipid droplet formation and confers ferroptosis resistance.
  22. An exhausted-like microglial population accumulates in aged and APOE4 genotype Alzheimer's brains.
  23. Baseline immune characteristics linked to pneumococcal vaccine responsiveness in older adults.
  24. IKKε and TBK1 prevent RIPK1 dependent and independent inflammation.
  25. Fatty acid synthesis suppresses dietary polyunsaturated fatty acid use.
  26. Nav1.7 as a chondrocyte regulator and therapeutic target for osteoarthritis.
  27. Derivation of human primordial germ cell-like cells in an embryonic-like culture.
  28. A novel arginine regulated PhD pathway.
  29. Circulating NK cells establish tissue residency upon acute infection of skin and mediate accelerated effector responses to secondary infection.
  30. Longevity interventions modulate mechanotransduction and extracellular matrix homeostasis in C. elegans.
  31. Sleep regulates innate immunity.
  32. Proteolytic activation of fatty acid synthase signals pan-stress resolution.
  33. Human and mouse peritoneal macrophages and dendritic cells compared.
  34. Identification of a chemical cocktail that drives the maturation of human neurons.
  35. Multi-ancestry genome-wide association study of major depression aids locus discovery, fine mapping, gene prioritization and causal inference.
  36. Reduction of DHHC5-mediated beclin 1 S-palmitoylation underlies autophagy decline in aging.
  37. Cyclical palmitoylation regulates TLR9 signalling and systemic autoimmunity in mice.
  38. ABCG2 is an itaconate exporter that limits antibacterial innate immunity by alleviating TFEB-dependent lysosomal biogenesis.
  39. Transient inhibition of 53BP1 increases the frequency of targeted integration in human hematopoietic stem and progenitor cells.
  40. A nanoemulsion targeting adipose hypertrophy and hyperplasia shows anti-obesity efficiency in female mice.
  41. Metabolic switch regulates lineage plasticity and induces synthetic lethality in triple-negative breast cancer.
  42. 15-Lipoxygenase promotes resolution of inflammation in lymphedema by controlling Treg cell function through IFN-β.
  43. Innate immune and proinflammatory signals activate the Hippo pathway via a Tak1-STRIPAK-Tao axis.
  44. MTCH2 cooperates with MFN2 and lysophosphatidic acid synthesis to sustain mitochondrial fusion.
  45. The high-dimensional space of human diseases built from diagnosis records and mapped to genetic loci.
  46. MCT1-governed pyruvate metabolism is essential for antibody class-switch recombination through H3K27 acetylation.
  47. IL-10-expressing CAR T cells resist dysfunction and mediate durable clearance of solid tumors and metastases.
  48. Nuclear disasters-in-waiting.
  49. Mic19 depletion impairs endoplasmic reticulum-mitochondrial contacts and mitochondrial lipid metabolism and triggers liver disease.
  50. Ribosomal profiling of human endogenous retroviruses in healthy tissues.
  51. The polyketide to fatty acid transition in the evolution of animal lipid metabolism.
  52. Gut microbial metabolite facilitates colorectal cancer development via ferroptosis inhibition.
  53. Cholesterol modulates type I/II TGF-β receptor complexes and alters the balance between Smad and Akt signaling in hepatocytes.
  54. FOXP3+ regulatory T cell perturbation mediated by the IFNγ-STAT1-IFITM3 feedback loop is essential for anti-tumor immunity.
  55. FOXO1-mediated lipid metabolism maintains mammalian embryos in dormancy.
  56. Secreted IgM modulates IL-10 expression in B cells.
  57. Oligodendrocyte calcium signaling promotes actin-dependent myelin sheath extension.
  58. A natural biogenic nanozyme for scavenging superoxide radicals.
  59. Beyond integrated care for older adults.
  60. Mutant p53 gains oncogenic functions through a chromosomal instability-induced cytosolic DNA response.
  61. A TLR4/TRAF6-dependent signaling pathway mediates NCoR coactivator complex formation for inflammatory gene activation.
  62. MAPS: pathologist-level cell type annotation from tissue images through machine learning.
  63. Inferring super-resolution tissue architecture by integrating spatial transcriptomics with histology.
  1. Nat Commun. 2024 Jan 04. 15(1): 292
    The glue that holds us together.
      
    DOI:  https://doi.org/10.1038/s41467-023-44476-5
  2. Nat Commun. 2024 Jan 03. 15(1): 212
    A good-for-something second brain.
      
    DOI:  https://doi.org/10.1038/s41467-023-44472-9
  3. Nat Commun. 2024 Jan 05. 15(1): 306
    Nature Communications from the point of view of our very first authors.
      
    DOI:  https://doi.org/10.1038/s41467-023-44470-x
  4. Nat Immunol. 2024 Jan;25(1): 3
    Immune imprinting.
    Ioana Visan.
      
    DOI:  https://doi.org/10.1038/s41590-023-01729-1
  5. Science. 2024 Jan 05. 383(6678): 122
    The call of activism.
    Andrew Sharo.
      
    DOI:  https://doi.org/10.1126/science.adn7829
  6. Nat Immunol. 2024 Jan;25(1): 3
    Fructose sweetens antitumor responses.
    Stephanie Houston.
      
    DOI:  https://doi.org/10.1038/s41590-023-01730-8
  7. Nat Immunol. 2024 Jan;25(1): 4-6
    Epigenetic checkpoints regulate the fate and function of CAR-T cells.
    Monica Casucci, Chiara Bonini, Eliana Ruggiero.
      
    DOI:  https://doi.org/10.1038/s41590-023-01708-6
  8. Nat Immunol. 2024 Jan 03.
    A type 1 immunity-restricted promoter of the IL-33 receptor gene directs antiviral T-cell responses.
    Tobias M Brunner, Sebastian Serve, Anna-Friederike Marx, Jelizaveta Fadejeva, Philippe Saikali, Maria Dzamukova, Nayar Durán-Hernández, Christoph Kommer, Frederik Heinrich, Pawel Durek, Gitta A Heinz, Thomas Höfer, Mir-Farzin Mashreghi, Ralf Kühn, Daniel D Pinschewer, Max Löhning.
      The pleiotropic alarmin interleukin-33 (IL-33) drives type 1, type 2 and regulatory T-cell responses via its receptor ST2. Subset-specific differences in ST2 expression intensity and dynamics suggest that transcriptional regulation is key in orchestrating the context-dependent activity of IL-33-ST2 signaling in T-cell immunity. Here, we identify a previously unrecognized alternative promoter in mice and humans that is located far upstream of the curated ST2-coding gene and drives ST2 expression in type 1 immunity. Mice lacking this promoter exhibit a selective loss of ST2 expression in type 1- but not type 2-biased T cells, resulting in impaired expansion of cytotoxic T cells (CTLs) and T-helper 1 cells upon viral infection. T-cell-intrinsic IL-33 signaling via type 1 promoter-driven ST2 is critical to generate a clonally diverse population of antiviral short-lived effector CTLs. Thus, lineage-specific alternative promoter usage directs alarmin responsiveness in T-cell subsets and offers opportunities for immune cell-specific targeting of the IL-33-ST2 axis in infections and inflammatory diseases.
    DOI:  https://doi.org/10.1038/s41590-023-01697-6
  9. Nat Immunol. 2024 Jan 03.
    Type 1 or type 2 lineage-specific promoters regulate expression of the IL-33 receptor in T cells.
      
    DOI:  https://doi.org/10.1038/s41590-023-01706-8
  10. Nat Immunol. 2024 Jan;25(1): 66-76
    CD4+ T cell immunity is dependent on an intrinsic stem-like program.
    Dawei Zou, Zheng Yin, Stephanie G Yi, Guohua Wang, Yang Guo, Xiang Xiao, Shuang Li, Xiaolong Zhang, Nancy M Gonzalez, Laurie J Minze, Lin Wang, Stephen T C Wong, A Osama Gaber, Rafik M Ghobrial, Xian C Li, Wenhao Chen.
      CD4+ T cells are central to various immune responses, but the molecular programs that drive and maintain CD4+ T cell immunity are not entirely clear. Here we identify a stem-like program that governs the CD4+ T cell response in transplantation models. Single-cell-transcriptomic analysis revealed that naive alloantigen-specific CD4+ T cells develop into TCF1hi effector precursor (TEP) cells and TCF1-CXCR6+ effectors in transplant recipients. The TCF1-CXCR6+CD4+ effectors lose proliferation capacity and do not reject allografts upon adoptive transfer into secondary hosts. By contrast, the TCF1hiCD4+ TEP cells have dual features of self-renewal and effector differentiation potential, and allograft rejection depends on continuous replenishment of TCF1-CXCR6+ effectors from TCF1hiCD4+ TEP cells. Mechanistically, TCF1 sustains the CD4+ TEP cell population, whereas the transcription factor IRF4 and the glycolytic enzyme LDHA govern the effector differentiation potential of CD4+ TEP cells. Deletion of IRF4 or LDHA in T cells induces transplant acceptance. These findings unravel a stem-like program that controls the self-renewal capacity and effector differentiation potential of CD4+ TEP cells and have implications for T cell-related immunotherapies.
    DOI:  https://doi.org/10.1038/s41590-023-01682-z
  11. Nat Commun. 2024 Jan 02. 15(1): 93
    TMEM55B links autophagy flux, lysosomal repair, and TFE3 activation in response to oxidative stress.
    Eutteum Jeong, Rose Willett, Alberto Rissone, Martina La Spina, Rosa Puertollano.
      Lysosomes have emerged as critical regulators of cellular homeostasis. Here we show that the lysosomal protein TMEM55B contributes to restore cellular homeostasis in response to oxidative stress by three different mechanisms: (1) TMEM55B mediates NEDD4-dependent PLEKHM1 ubiquitination, causing PLEKHM1 proteasomal degradation and halting autophagosome/lysosome fusion; (2) TMEM55B promotes recruitment of components of the ESCRT machinery to lysosomal membranes to stimulate lysosomal repair; and (3) TMEM55B sequesters the FLCN/FNIP complex to facilitate translocation of the transcription factor TFE3 to the nucleus, allowing expression of transcriptional programs that enable cellular adaptation to stress. Knockout of tmem55 genes in zebrafish embryos increases their susceptibility to oxidative stress, causing early death of tmem55-KO animals in response to arsenite toxicity. Altogether, our work identifies a role for TMEM55B as a molecular sensor that coordinates autophagosome degradation, lysosomal repair, and activation of stress responses.
    DOI:  https://doi.org/10.1038/s41467-023-44316-6
  12. Nat Cell Biol. 2024 Jan 02.
    Vitamin B12 produced by gut bacteria modulates cholinergic signalling.
    Woo Kyu Kang, Jeremy T Florman, Antonia Araya, Bennett W Fox, Andrea Thackeray, Frank C Schroeder, Albertha J M Walhout, Mark J Alkema.
      A growing body of evidence indicates that gut microbiota influence brain function and behaviour. However, the molecular basis of how gut bacteria modulate host nervous system function is largely unknown. Here we show that vitamin B12-producing bacteria that colonize the intestine can modulate excitatory cholinergic signalling and behaviour in the host Caenorhabditis elegans. Here we demonstrate that vitamin B12 reduces cholinergic signalling in the nervous system through rewiring of the methionine (Met)/S-adenosylmethionine cycle in the intestine. We identify a conserved metabolic crosstalk between the methionine/S-adenosylmethionine cycle and the choline-oxidation pathway. In addition, we show that metabolic rewiring of these pathways by vitamin B12 reduces cholinergic signalling by limiting the availability of free choline required by neurons to synthesize acetylcholine. Our study reveals a gut-brain communication pathway by which enteric bacteria modulate host behaviour and may affect neurological health.
    DOI:  https://doi.org/10.1038/s41556-023-01299-2
  13. Nat Rev Immunol. 2024 Jan 04.
    Ancient DNA reveals evolutionary origins of autoimmune diseases.
    William Barrie, Evan K Irving-Pease, Eske Willerslev, Astrid K N Iversen, Lars Fugger.
      
    DOI:  https://doi.org/10.1038/s41577-023-00983-6
  14. Nat Commun. 2024 Jan 02. 15(1): 123
    From lab to life: how wearable devices can improve health equity.
    Jessica R Walter, Shuai Xu, John A Rogers.
      
    DOI:  https://doi.org/10.1038/s41467-023-44634-9
  15. Nat Commun. 2024 Jan 03. 15(1): 222
    Feeding the future global population.
      
    DOI:  https://doi.org/10.1038/s41467-023-44588-y
  16. Nat Commun. 2024 Jan 05. 15(1): 299
    Direct translation of incoming retroviral genomes.
    Julia Köppke, Luise-Elektra Keller, Michelle Stuck, Nicolas D Arnow, Norbert Bannert, Joerg Doellinger, Oya Cingöz.
      Viruses that carry a positive-sense, single-stranded (+ssRNA) RNA translate their genomes soon after entering the host cell to produce viral proteins, with the exception of retroviruses. A distinguishing feature of retroviruses is reverse transcription, where the +ssRNA genome serves as a template to synthesize a double-stranded DNA copy that subsequently integrates into the host genome. As retroviral RNAs are produced by the host cell transcriptional machinery and are largely indistinguishable from cellular mRNAs, we investigated the potential of incoming retroviral genomes to directly express proteins. Here we show through multiple, complementary methods that retroviral genomes are translated after entry. Our findings challenge the notion that retroviruses require reverse transcription to produce viral proteins. Synthesis of retroviral proteins in the absence of productive infection has significant implications for basic retrovirology, immune responses and gene therapy applications.
    DOI:  https://doi.org/10.1038/s41467-023-44501-7
  17. Cell Metab. 2024 Jan 02. pii: S1550-4131(23)00451-5. [Epub ahead of print]36(1): 90-102.e7
    Repression of latent NF-κB enhancers by PDX1 regulates β cell functional heterogeneity.
    Benjamin J Weidemann, Biliana Marcheva, Mikoto Kobayashi, Chiaki Omura, Marsha V Newman, Yumiko Kobayashi, Nathan J Waldeck, Mark Perelis, Louise Lantier, Owen P McGuinness, Kathryn Moynihan Ramsey, Roland W Stein, Joseph Bass.
      Interactions between lineage-determining and activity-dependent transcription factors determine single-cell identity and function within multicellular tissues through incompletely known mechanisms. By assembling a single-cell atlas of chromatin state within human islets, we identified β cell subtypes governed by either high or low activity of the lineage-determining factor pancreatic duodenal homeobox-1 (PDX1). β cells with reduced PDX1 activity displayed increased chromatin accessibility at latent nuclear factor κB (NF-κB) enhancers. Pdx1 hypomorphic mice exhibited de-repression of NF-κB and impaired glucose tolerance at night. Three-dimensional analyses in tandem with chromatin immunoprecipitation (ChIP) sequencing revealed that PDX1 silences NF-κB at circadian and inflammatory enhancers through long-range chromatin contacts involving SIN3A. Conversely, Bmal1 ablation in β cells disrupted genome-wide PDX1 and NF-κB DNA binding. Finally, antagonizing the interleukin (IL)-1β receptor, an NF-κB target, improved insulin secretion in Pdx1 hypomorphic islets. Our studies reveal functional subtypes of single β cells defined by a gradient in PDX1 activity and identify NF-κB as a target for insulinotropic therapy.
    Keywords:  IL-1β; NF-κB; PDX1; chromatin; circadian; diabetes; inflammation; insulin; p65; β cells
    DOI:  https://doi.org/10.1016/j.cmet.2023.11.018
  18. Nat Commun. 2024 Jan 02. 15(1): 15
    Cell-type differential targeting of SETDB1 prevents aberrant CTCF binding, chromatin looping, and cis-regulatory interactions.
    Phoebe Lut Fei Tam, Ming Fung Cheung, Lu Yan Chan, Danny Leung.
      SETDB1 is an essential histone methyltransferase that deposits histone H3 lysine 9 trimethylation (H3K9me3) to transcriptionally repress genes and repetitive elements. The function of differential H3K9me3 enrichment between cell-types remains unclear. Here, we demonstrate mutual exclusivity of H3K9me3 and CTCF across mouse tissues from different developmental timepoints. We analyze SETDB1 depleted cells and discover that H3K9me3 prevents aberrant CTCF binding independently of DNA methylation and H3K9me2. Such sites are enriched with SINE B2 retrotransposons. Moreover, analysis of higher-order genome architecture reveals that large chromatin structures including topologically associated domains and subnuclear compartments, remain intact in SETDB1 depleted cells. However, chromatin loops and local 3D interactions are disrupted, leading to transcriptional changes by modifying pre-existing chromatin landscapes. Specific genes with altered expression show differential interactions with dysregulated cis-regulatory elements. Collectively, we find that cell-type specific targets of SETDB1 maintain cellular identities by modulating CTCF binding, which shape nuclear architecture and transcriptomic networks.
    DOI:  https://doi.org/10.1038/s41467-023-44578-0
  19. Nat Commun. 2024 Jan 02. 15(1): 97
    Myeloid-derived grancalcin instigates obesity-induced insulin resistance and metabolic inflammation in male mice.
    Tian Su, Yue He, Yan Huang, Mingsheng Ye, Qi Guo, Ye Xiao, Guangping Cai, Linyun Chen, Changjun Li, Haiyan Zhou, Xianghang Luo.
      The crosstalk between the bone and adipose tissue is known to orchestrate metabolic homeostasis, but the underlying mechanisms are largely unknown. Herein, we find that GCA + (grancalcin) immune cells accumulate in the bone marrow and release a considerable amount of GCA into circulation during obesity. Genetic deletion of Gca in myeloid cells attenuates metabolic dysfunction in obese male mice, whereas injection of recombinant GCA into male mice causes adipose tissue inflammation and insulin resistance. Mechanistically, we found that GCA binds to the Prohibitin-2 (PHB2) receptor on adipocytes and activates the innate and adaptive immune response of adipocytes via the PAK1-NF-κB signaling pathway, thus provoking the infiltration of inflammatory immune cells. Moreover, we show that GCA-neutralizing antibodies improve adipose tissue inflammation and insulin sensitivity in obese male mice. Together, these observations define a mechanism whereby bone marrow factor GCA initiates adipose tissue inflammation and insulin resistance, showing that GCA could be a potential target to treat metainflammation.
    DOI:  https://doi.org/10.1038/s41467-023-43787-x
  20. Nat Commun. 2024 Jan 04. 15(1): 252
    Cullin5 drives experimental asthma exacerbations by modulating alveolar macrophage antiviral immunity.
    Haibo Zhang, Keke Xue, Wen Li, Xinyi Yang, Yusen Gou, Xiao Su, Feng Qian, Lei Sun.
      Asthma exacerbations caused by respiratory viral infections are a serious global health problem. Impaired antiviral immunity is thought to contribute to the pathogenesis, but the underlying mechanisms remain understudied. Here using mouse models we find that Cullin5 (CUL5), a key component of Cullin-RING E3 ubiquitin ligase 5, is upregulated and associated with increased neutrophil count and influenza-induced exacerbations of house dust mite-induced asthma. By contrast, CUL5 deficiency mitigates neutrophilic lung inflammation and asthma exacerbations by augmenting IFN-β production. Mechanistically, following thymic stromal lymphopoietin stimulation, CUL5 interacts with O-GlcNAc transferase (OGT) and induces Lys48-linked polyubiquitination of OGT, blocking the effect of OGT on mitochondrial antiviral-signaling protein O-GlcNAcylation and RIG-I signaling activation. Our results thus suggest that, in mouse models, pre-existing allergic injury induces CUL5 expression, impairing antiviral immunity and promoting neutrophilic inflammation for asthma exacerbations. Targeting of the CUL5/IFN-β signaling axis may thereby serve as a possible therapy for treating asthma exacerbations.
    DOI:  https://doi.org/10.1038/s41467-023-44168-0
  21. Nat Commun. 2024 Jan 02. 15(1): 79
    Cell cycle arrest induces lipid droplet formation and confers ferroptosis resistance.
    Hyemin Lee, Amber Horbath, Lavanya Kondiparthi, Jitendra Kumar Meena, Guang Lei, Shayani Dasgupta, Xiaoguang Liu, Li Zhuang, Pranavi Koppula, Mi Li, Iqbal Mahmud, Bo Wei, Philip L Lorenzi, Khandan Keyomarsi, Masha V Poyurovsky, Kellen Olszewski, Boyi Gan.
      How cells coordinate cell cycling with cell survival and death remains incompletely understood. Here, we show that cell cycle arrest has a potent suppressive effect on ferroptosis, a form of regulated cell death induced by overwhelming lipid peroxidation at cellular membranes. Mechanistically, cell cycle arrest induces diacylglycerol acyltransferase (DGAT)-dependent lipid droplet formation to sequester excessive polyunsaturated fatty acids (PUFAs) that accumulate in arrested cells in triacylglycerols (TAGs), resulting in ferroptosis suppression. Consequently, DGAT inhibition orchestrates a reshuffling of PUFAs from TAGs to phospholipids and re-sensitizes arrested cells to ferroptosis. We show that some slow-cycling antimitotic drug-resistant cancer cells, such as 5-fluorouracil-resistant cells, have accumulation of lipid droplets and that combined treatment with ferroptosis inducers and DGAT inhibitors effectively suppresses the growth of 5-fluorouracil-resistant tumors by inducing ferroptosis. Together, these results reveal a role for cell cycle arrest in driving ferroptosis resistance and suggest a ferroptosis-inducing therapeutic strategy to target slow-cycling therapy-resistant cancers.
    DOI:  https://doi.org/10.1038/s41467-023-44412-7
  22. Immunity. 2023 Dec 22. pii: S1074-7613(23)00532-0. [Epub ahead of print]
    An exhausted-like microglial population accumulates in aged and APOE4 genotype Alzheimer's brains.
    Alon Millet, Jose Henrique Ledo, Sohail F Tavazoie.
      The dominant risk factors for late-onset Alzheimer's disease (AD) are advanced age and the APOE4 genetic variant. To examine how these factors alter neuroimmune function, we generated an integrative, longitudinal single-cell atlas of brain immune cells in AD model mice bearing the three common human APOE alleles. Transcriptomic and chromatin accessibility analyses identified a reactive microglial population defined by the concomitant expression of inflammatory signals and cell-intrinsic stress markers whose frequency increased with age and APOE4 burden. An analogous population was detectable in the brains of human AD patients, including in the cortical tissue, using multiplexed spatial transcriptomics. This population, which we designate as terminally inflammatory microglia (TIM), exhibited defects in amyloid-β clearance and altered cell-cell communication during aducanumab treatment. TIM may represent an exhausted-like state for inflammatory microglia in the AD milieu that contributes to AD risk and pathology in APOE4 carriers and the elderly, thus presenting a potential therapeutic target for AD.
    Keywords:  APOE; Alzheimer's disease; TIM; microglia; single cell
    DOI:  https://doi.org/10.1016/j.immuni.2023.12.001
  23. Nat Immunol. 2024 Jan 05.
    Baseline immune characteristics linked to pneumococcal vaccine responsiveness in older adults.
      
    DOI:  https://doi.org/10.1038/s41590-023-01737-1
  24. Nat Commun. 2024 Jan 02. 15(1): 130
    IKKε and TBK1 prevent RIPK1 dependent and independent inflammation.
    Remzi Onur Eren, Göksu Gökberk Kaya, Robin Schwarzer, Manolis Pasparakis.
      TBK1 and IKKε regulate multiple cellular processes including anti-viral type-I interferon responses, metabolism and TNF receptor signaling. However, the relative contributions and potentially redundant functions of IKKε and TBK1 in cell death, inflammation and tissue homeostasis remain poorly understood. Here we show that IKKε compensates for the loss of TBK1 kinase activity to prevent RIPK1-dependent and -independent inflammation in mice. Combined inhibition of IKKε and TBK1 kinase activities caused embryonic lethality that was rescued by heterozygous expression of kinase-inactive RIPK1. Adult mice expressing kinase-inactive versions of IKKε and TBK1 developed systemic inflammation that was induced by both RIPK1-dependent and -independent mechanisms. Combined inhibition of IKKε and TBK1 kinase activities in myeloid cells induced RIPK1-dependent cell death and systemic inflammation mediated by IL-1 family cytokines. Tissue-specific studies showed that IKKε and TBK1 were required to prevent cell death and inflammation in the intestine but were dispensable for liver and skin homeostasis. Together, these findings revealed that IKKε and TBK1 exhibit tissue-specific functions that are important to prevent cell death and inflammation and maintain tissue homeostasis.
    DOI:  https://doi.org/10.1038/s41467-023-44372-y
  25. Nat Commun. 2024 Jan 02. 15(1): 45
    Fatty acid synthesis suppresses dietary polyunsaturated fatty acid use.
    Anna Worthmann, Julius Ridder, Sharlaine Y L Piel, Ioannis Evangelakos, Melina Musfeldt, Hannah Voß, Marie O'Farrell, Alexander W Fischer, Sangeeta Adak, Monica Sundd, Hasibullah Siffeti, Friederike Haumann, Katja Kloth, Tatjana Bierhals, Markus Heine, Paul Pertzborn, Mira Pauly, Julia-Josefine Scholz, Suman Kundu, Marceline M Fuh, Axel Neu, Klaus Tödter, Maja Hempel, Uwe Knippschild, Clay F Semenkovich, Hartmut Schlüter, Joerg Heeren, Ludger Scheja, Christian Kubisch, Christian Schlein.
      Dietary polyunsaturated fatty acids (PUFA) are increasingly recognized for their health benefits, whereas a high production of endogenous fatty acids - a process called de novo lipogenesis (DNL) - is closely linked to metabolic diseases. Determinants of PUFA incorporation into complex lipids are insufficiently understood and may influence the onset and progression of metabolic diseases. Here we show that fatty acid synthase (FASN), the key enzyme of DNL, critically determines the use of dietary PUFA in mice and humans. Moreover, the combination of FASN inhibition and PUFA-supplementation decreases liver triacylglycerols (TAG) in mice fed with high-fat diet. Mechanistically, FASN inhibition causes higher PUFA uptake via the lysophosphatidylcholine transporter MFSD2A, and a diacylglycerol O-acyltransferase 2 (DGAT2)-dependent incorporation of PUFA into TAG. Overall, the outcome of PUFA supplementation may depend on the degree of endogenous DNL and combining PUFA supplementation and FASN inhibition might be a promising approach to target metabolic disease.
    DOI:  https://doi.org/10.1038/s41467-023-44364-y
  26. Nature. 2024 Jan 03.
    Nav1.7 as a chondrocyte regulator and therapeutic target for osteoarthritis.
    Wenyu Fu, Dmytro Vasylyev, Yufei Bi, Mingshuang Zhang, Guodong Sun, Asya Khleborodova, Guiwu Huang, Libo Zhao, Renpeng Zhou, Yonggang Li, Shujun Liu, Xianyi Cai, Wenjun He, Min Cui, Xiangli Zhao, Aubryanna Hettinghouse, Julia Good, Ellen Kim, Eric Strauss, Philipp Leucht, Ran Schwarzkopf, Edward X Guo, Jonathan Samuels, Wenhuo Hu, Mukundan Attur, Stephen G Waxman, Chuan-Ju Liu.
      Osteoarthritis (OA) is the most common joint disease. Currently there are no effective methods that simultaneously prevent joint degeneration and reduce pain1. Although limited evidence suggests the existence of voltage-gated sodium channels (VGSCs) in chondrocytes2, their expression and function in chondrocytes and in OA remain essentially unknown. Here we identify Nav1.7 as an OA-associated VGSC and demonstrate that human OA chondrocytes express functional Nav1.7 channels, with a density of 0.1 to 0.15 channels per µm2 and 350 to 525 channels per cell. Serial genetic ablation of Nav1.7 in multiple mouse models demonstrates that Nav1.7 expressed in dorsal root ganglia neurons is involved in pain, whereas Nav1.7 in chondrocytes regulates OA progression. Pharmacological blockade of Nav1.7 with selective or clinically used pan-Nav channel blockers significantly ameliorates the progression of structural joint damage, and reduces OA pain behaviour. Mechanistically, Nav1.7 blockers regulate intracellular Ca2+ signalling and the chondrocyte secretome, which in turn affects chondrocyte biology and OA progression. Identification of Nav1.7 as a novel chondrocyte-expressed, OA-associated channel uncovers a dual target for the development of disease-modifying and non-opioid pain relief treatment for OA.
    DOI:  https://doi.org/10.1038/s41586-023-06888-7
  27. Nat Commun. 2024 Jan 02. 15(1): 167
    Derivation of human primordial germ cell-like cells in an embryonic-like culture.
    Sajedeh Nasr Esfahani, Yi Zheng, Auriana Arabpour, Agnes M Resto Irizarry, Norio Kobayashi, Xufeng Xue, Yue Shao, Cheng Zhao, Nicole L Agranonik, Megan Sparrow, Timothy J Hunt, Jared Faith, Mary Jasmine Lara, Qiu Ya Wu, Sherman Silber, Sophie Petropoulos, Ran Yang, Kenneth R Chien, Amander T Clark, Jianping Fu.
      Primordial germ cells (PGCs) are the embryonic precursors of sperm and eggs. They transmit genetic and epigenetic information across generations. Given the prominent role of germline defects in diseases such as infertility, detailed understanding of human PGC (hPGC) development has important implications in reproductive medicine and studying human evolution. Yet, hPGC specification remains an elusive process. Here, we report the induction of hPGC-like cells (hPGCLCs) in a bioengineered human pluripotent stem cell (hPSC) culture that mimics peri-implantation human development. In this culture, amniotic ectoderm-like cells (AMLCs), derived from hPSCs, induce hPGCLC specification from hPSCs through paracrine signaling downstream of ISL1. Our data further show functional roles of NODAL, WNT, and BMP signaling in hPGCLC induction. hPGCLCs are successfully derived from eight non-obstructive azoospermia (NOA) participant-derived hPSC lines using this biomimetic platform, demonstrating its promise for screening applications.
    DOI:  https://doi.org/10.1038/s41467-023-43871-2
  28. Nat Commun. 2024 Jan 03. 15(1): 213
    A novel arginine regulated PhD pathway.
      
    DOI:  https://doi.org/10.1038/s41467-023-44473-8
  29. Immunity. 2023 Dec 22. pii: S1074-7613(23)00500-9. [Epub ahead of print]
    Circulating NK cells establish tissue residency upon acute infection of skin and mediate accelerated effector responses to secondary infection.
    Tommaso Torcellan, Christin Friedrich, Rémi Doucet-Ladevèze, Thomas Ossner, Virgínia Visaconill Solé, Sofie Riedmann, Milas Ugur, Fabian Imdahl, Stephan P Rosshart, Sebastian J Arnold, Mercedes Gomez de Agüero, Nicola Gagliani, Richard A Flavell, Simone Backes, Wolfgang Kastenmüller, Georg Gasteiger.
      Natural killer (NK) cells are present in the circulation and can also be found residing in tissues, and these populations exhibit distinct developmental requirements and are thought to differ in terms of ontogeny. Here, we investigate whether circulating conventional NK (cNK) cells can develop into long-lived tissue-resident NK (trNK) cells following acute infections. We found that viral and bacterial infections of the skin triggered the recruitment of cNK cells and their differentiation into Tcf1hiCD69hi trNK cells that share transcriptional similarity with CD56brightTCF1hi NK cells in human tissues. Skin trNK cells arose from interferon (IFN)-γ-producing effector cells and required restricted expression of the transcriptional regulator Blimp1 to optimize Tcf1-dependent trNK cell formation. Upon secondary infection, trNK cells rapidly gained effector function and mediated an accelerated NK cell response. Thus, cNK cells redistribute and permanently position at sites of previous infection via a mechanism promoting tissue residency that is distinct from Hobit-dependent developmental paths of NK cells and ILC1 seeding tissues during ontogeny.
    Keywords:  Staphylococcus aureus; infection; innate immune memory; innate lymphoid cells; natural killer cells; tissue immunity; tissue-resident lymphocytes; trained immunity; vaccination; vaccinia virus
    DOI:  https://doi.org/10.1016/j.immuni.2023.11.018
  30. Nat Commun. 2024 Jan 04. 15(1): 276
    Longevity interventions modulate mechanotransduction and extracellular matrix homeostasis in C. elegans.
    Alina C Teuscher, Cyril Statzer, Anita Goyala, Seraina A Domenig, Ingmar Schoen, Max Hess, Alexander M Hofer, Andrea Fossati, Viola Vogel, Orcun Goksel, Ruedi Aebersold, Collin Y Ewald.
      Dysfunctional extracellular matrices (ECM) contribute to aging and disease. Repairing dysfunctional ECM could potentially prevent age-related pathologies. Interventions promoting longevity also impact ECM gene expression. However, the role of ECM composition changes in healthy aging remains unclear. Here we perform proteomics and in-vivo monitoring to systematically investigate ECM composition (matreotype) during aging in C. elegans revealing three distinct collagen dynamics. Longevity interventions slow age-related collagen stiffening and prolong the expression of collagens that are turned over. These prolonged collagen dynamics are mediated by a mechanical feedback loop of hemidesmosome-containing structures that span from the exoskeletal ECM through the hypodermis, basement membrane ECM, to the muscles, coupling mechanical forces to adjust ECM gene expression and longevity via the transcriptional co-activator YAP-1 across tissues. Our results provide in-vivo evidence that coordinated ECM remodeling through mechanotransduction is required and sufficient to promote longevity, offering potential avenues for interventions targeting ECM dynamics.
    DOI:  https://doi.org/10.1038/s41467-023-44409-2
  31. Nat Immunol. 2024 Jan;25(1): 3
    Sleep regulates innate immunity.
    Laurie A Dempsey.
      
    DOI:  https://doi.org/10.1038/s41590-023-01727-3
  32. Nat Metab. 2024 Jan 02.
    Proteolytic activation of fatty acid synthase signals pan-stress resolution.
    Hai Wei, Yi M Weaver, Chendong Yang, Yuan Zhang, Guoli Hu, Courtney M Karner, Matthew Sieber, Ralph J DeBerardinis, Benjamin P Weaver.
      Chronic stress and inflammation are both outcomes and major drivers of many human diseases. Sustained responsiveness despite mitigation suggests a failure to sense resolution of the stressor. Here we show that a proteolytic cleavage event of fatty acid synthase (FASN) activates a global cue for stress resolution in Caenorhabditis elegans. FASN is well established for biosynthesis of the fatty acid palmitate. Our results demonstrate FASN promoting an anti-inflammatory profile apart from palmitate synthesis. Redox-dependent proteolysis of limited amounts of FASN by caspase activates a C-terminal fragment sufficient to downregulate multiple aspects of stress responsiveness, including gene expression, metabolic programs and lipid droplets. The FASN C-terminal fragment signals stress resolution in a cell non-autonomous manner. Consistent with these findings, FASN processing is also seen in well-fed but not fasted male mouse liver. As downregulation of stress responses is critical to health, our findings provide a potential pathway to control diverse aspects of stress responses.
    DOI:  https://doi.org/10.1038/s42255-023-00939-z
  33. Nat Immunol. 2024 Jan;25(1): 17-18
    Human and mouse peritoneal macrophages and dendritic cells compared.
      
    DOI:  https://doi.org/10.1038/s41590-023-01709-5
  34. Nat Biotechnol. 2024 Jan 02.
    Identification of a chemical cocktail that drives the maturation of human neurons.
      
    DOI:  https://doi.org/10.1038/s41587-023-02044-8
  35. Nat Genet. 2024 Jan 04.
    Multi-ancestry genome-wide association study of major depression aids locus discovery, fine mapping, gene prioritization and causal inference.
    PGC-MDD Working Group
      Most genome-wide association studies (GWAS) of major depression (MD) have been conducted in samples of European ancestry. Here we report a multi-ancestry GWAS of MD, adding data from 21 cohorts with 88,316 MD cases and 902,757 controls to previously reported data. This analysis used a range of measures to define MD and included samples of African (36% of effective sample size), East Asian (26%) and South Asian (6%) ancestry and Hispanic/Latin American participants (32%). The multi-ancestry GWAS identified 53 significantly associated novel loci. For loci from GWAS in European ancestry samples, fewer than expected were transferable to other ancestry groups. Fine mapping benefited from additional sample diversity. A transcriptome-wide association study identified 205 significantly associated novel genes. These findings suggest that, for MD, increasing ancestral and global diversity in genetic studies may be particularly important to ensure discovery of core genes and inform about transferability of findings.
    DOI:  https://doi.org/10.1038/s41588-023-01596-4
  36. Nat Struct Mol Biol. 2024 Jan 04.
    Reduction of DHHC5-mediated beclin 1 S-palmitoylation underlies autophagy decline in aging.
    Rui Guo, Jianping Liu, Xia Min, Wen Zeng, Bing Shan, Mengmeng Zhang, Zhuohao He, Yaoyang Zhang, Kaiwen He, Junying Yuan, Daichao Xu.
      Autophagy is a lysosome-dependent degradation pathway essential for cellular homeostasis, which decreases with age. However, it is unclear how aging induces autophagy decline. Here we show the role of protein S-palmitoylation in autophagy. We identify the palmitoyl acyltransferase DHHC5 as a regulator of autophagy by mediating the palmitoylation of beclin 1, which in turn promotes the formation of ATG14L-containing class III phosphatidylinositol-3-kinase complex I and its lipid kinase activity by promoting the hydrophobic interactions between beclin 1 and adapter proteins ATG14L and VPS15. In aging brains of human and nonhuman primate, the levels of DHHC5 exhibit a marked decrease in expression. We show that DHHC5 deficiency in neurons leads to reduced cellular protein homeostasis in two established murine models of Alzheimer's disease, which exaggerates neurodegeneration in an autophagy-dependent manner. These findings identify reduction of DHHC5-mediated beclin 1 S-palmitoylation as an underlying mechanism by which aging induces autophagy decline.
    DOI:  https://doi.org/10.1038/s41594-023-01163-9
  37. Nat Commun. 2024 Jan 02. 15(1): 1
    Cyclical palmitoylation regulates TLR9 signalling and systemic autoimmunity in mice.
    Hai Ni, Yinuo Wang, Kai Yao, Ling Wang, Jiancheng Huang, Yongfang Xiao, Hongyao Chen, Bo Liu, Cliff Y Yang, Jijun Zhao.
      Toll-like receptor 9 (TLR9) recognizes self-DNA and plays intricate roles in systemic lupus erythematosus (SLE). However, the molecular mechanism regulating the endosomal TLR9 response is incompletely understood. Here, we report that palmitoyl-protein thioesterase 1 (PPT1) regulates systemic autoimmunity by removing S-palmitoylation from TLR9 in lysosomes. PPT1 promotes the secretion of IFNα by plasmacytoid dendritic cells (pDCs) and TNF by macrophages. Genetic deficiency in or chemical inhibition of PPT1 reduces anti-nuclear antibody levels and attenuates nephritis in B6.Sle1yaa mice. In healthy volunteers and patients with SLE, the PPT1 inhibitor, HDSF, reduces IFNα production ex vivo. Mechanistically, biochemical and mass spectrometry analyses demonstrated that TLR9 is S-palmitoylated at C258 and C265. Moreover, the protein acyltransferase, DHHC3, palmitoylates TLR9 in the Golgi, and regulates TLR9 trafficking to endosomes. Subsequent depalmitoylation by PPT1 facilitates the release of TLR9 from UNC93B1. Our results reveal a posttranslational modification cycle that controls TLR9 response and autoimmunity.
    DOI:  https://doi.org/10.1038/s41467-023-43650-z
  38. Cell Metab. 2024 Jan 02. pii: S1550-4131(23)00465-5. [Epub ahead of print]
    ABCG2 is an itaconate exporter that limits antibacterial innate immunity by alleviating TFEB-dependent lysosomal biogenesis.
    Chao Chen, Zhenxing Zhang, Caiyun Liu, Pengkai Sun, Ping Liu, Xinjian Li.
      Itaconate is a metabolite that synthesized from cis-aconitate in mitochondria and transported into the cytosol to exert multiple regulatory effects in macrophages. However, the mechanism by which itaconate exits from macrophages remains unknown. Using a genetic screen, we reveal that itaconate is exported from cytosol to extracellular space by ATP-binding cassette transporter G2 (ABCG2) in an ATPase-dependent manner in human and mouse macrophages. Elevation of transcription factor TFEB-dependent lysosomal biogenesis and antibacterial innate immunity are observed in inflammatory macrophages with deficiency of ABCG2-mediated itaconate export. Furthermore, deficiency of ABCG2-mediated itaconate export in macrophages promotes antibacterial innate immune defense in a mouse model of S. typhimurium infection. Thus, our findings identify ABCG2-mediated itaconate export as a key regulatory mechanism that limits TFEB-dependent lysosomal biogenesis and antibacterial innate immunity in inflammatory macrophages, implying the potential therapeutic utility of blocking itaconate export in treating human bacterial infections.
    Keywords:  ABCG2; TFEB; exporter; innate immunity; itaconate; lysosomal biogenesis; macrophages
    DOI:  https://doi.org/10.1016/j.cmet.2023.12.015
  39. Nat Commun. 2024 Jan 02. 15(1): 111
    Transient inhibition of 53BP1 increases the frequency of targeted integration in human hematopoietic stem and progenitor cells.
    Ron Baik, M Kyle Cromer, Steve E Glenn, Christopher A Vakulskas, Kay O Chmielewski, Amanda M Dudek, William N Feist, Julia Klermund, Suzette Shipp, Toni Cathomen, Daniel P Dever, Matthew H Porteus.
      Genome editing by homology directed repair (HDR) is leveraged to precisely modify the genome of therapeutically relevant hematopoietic stem and progenitor cells (HSPCs). Here, we present a new approach to increasing the frequency of HDR in human HSPCs by the delivery of an inhibitor of 53BP1 (named "i53") as a recombinant peptide. We show that the use of i53 peptide effectively increases the frequency of HDR-mediated genome editing at a variety of therapeutically relevant loci in HSPCs as well as other primary human cell types. We show that incorporating the use of i53 recombinant protein allows high frequencies of HDR while lowering the amounts of AAV6 needed by 8-fold. HDR edited HSPCs were capable of long-term and bi-lineage hematopoietic reconstitution in NSG mice, suggesting that i53 recombinant protein might be safely integrated into the standard CRISPR/AAV6-mediated genome editing protocol to gain greater numbers of edited cells for transplantation of clinically meaningful cell populations.
    DOI:  https://doi.org/10.1038/s41467-023-43413-w
  40. Nat Commun. 2024 Jan 02. 15(1): 72
    A nanoemulsion targeting adipose hypertrophy and hyperplasia shows anti-obesity efficiency in female mice.
    Yichao Lu, Zhenyu Luo, Huanli Zhou, Yingying Shi, Ying Zhu, Xuemeng Guo, Jiaxin Huang, Junlei Zhang, Xu Liu, Sijie Wang, Xinyu Shan, Hang Yin, Yongzhong Du, Qingpo Li, Jian You, Lihua Luo.
      Obesity often leads to severe medical complications. However, existing FDA-approved medications to combat obesity have limited effectiveness in reducing adiposity and often cause side effects. These medications primarily act on the central nervous system or disrupt fat absorption through the gastrointestinal tract. Adipose tissue enlargement involves adipose hyperplasia and hypertrophy, both of which correlate with increased reactive oxygen species (ROS) and hyperactivated X-box binding protein 1 (XBP1) in (pre)adipocytes. In this study, we demonstrate that KT-NE, a nanoemulsion loaded with the XBP1 inhibitor KIRA6 and α-Tocopherol, simultaneously alleviates aberrant endoplasmic reticulum stress and oxidative stress in (pre)adipocytes. As a result, KT-NE significantly inhibits abnormal adipogenic differentiation, reduces lipid droplet accumulation, restricts lipid droplet transfer, impedes obesity progression, and lowers the risk of obesity-associated non-alcoholic fatty liver disease in female mice with obesity. Furthermore, diverse administration routes of KT-NE impact its in vivo biodistribution and contribute to localized and/or systemic anti-obesity effectiveness.
    DOI:  https://doi.org/10.1038/s41467-023-44416-3
  41. Cell Metab. 2024 Jan 02. pii: S1550-4131(23)00455-2. [Epub ahead of print]36(1): 193-208.e8
    Metabolic switch regulates lineage plasticity and induces synthetic lethality in triple-negative breast cancer.
    Yingsheng Zhang, Meng-Ju Wu, Wan-Chi Lu, Yi-Chuan Li, Chun Ju Chang, Jer-Yen Yang.
      Metabolic reprogramming is key for cancer development, yet the mechanism that sustains triple-negative breast cancer (TNBC) cell growth despite deficient pyruvate kinase M2 (PKM2) and tumor glycolysis remains to be determined. Here, we find that deficiency in tumor glycolysis activates a metabolic switch from glycolysis to fatty acid β-oxidation (FAO) to fuel TNBC growth. We show that, in TNBC cells, PKM2 directly interacts with histone methyltransferase EZH2 to coordinately mediate epigenetic silencing of a carnitine transporter, SLC16A9. Inhibition of PKM2 leads to impaired EZH2 recruitment to SLC16A9, and in turn de-represses SLC16A9 expression to increase intracellular carnitine influx, programming TNBC cells to an FAO-dependent and luminal-like cell state. Together, these findings reveal a new metabolic switch that drives TNBC from a metabolically heterogeneous-lineage plastic cell state to an FAO-dependent-lineage committed cell state, where dual targeting of EZH2 and FAO induces potent synthetic lethality in TNBC.
    Keywords:  EZH2; PKM2; SLC16A9; induced synthetic lethality; lineage plasticity; metabolic reprogramming
    DOI:  https://doi.org/10.1016/j.cmet.2023.12.003
  42. Nat Commun. 2024 Jan 04. 15(1): 221
    15-Lipoxygenase promotes resolution of inflammation in lymphedema by controlling Treg cell function through IFN-β.
    A Zamora, M Nougué, L Verdu, E Balzan, T Draia-Nicolau, E Benuzzi, F Pujol, V Baillif, E Lacazette, F Morfoisse, J Galitzky, A Bouloumié, M Dubourdeau, B Chaput, N Fazilleau, J Malloizel-Delaunay, A Bura-Rivière, A C Prats, B Garmy-Susini.
      Lymphedema (LD) is characterized by the accumulation of interstitial fluid, lipids and inflammatory cell infiltrate in the limb. Here, we find that LD tissues from women who developed LD after breast cancer exhibit an inflamed gene expression profile. Lipidomic analysis reveals decrease in specialized pro-resolving mediators (SPM) generated by the 15-lipoxygenase (15-LO) in LD. In mice, the loss of SPM is associated with an increase in apoptotic regulatory T (Treg) cell number. In addition, the selective depletion of 15-LO in the lymphatic endothelium induces an aggravation of LD that can be rescued by Treg cell adoptive transfer or ALOX15-expressing lentivector injections. Mechanistically, exogenous injections of the pro-resolving cytokine IFN-β restores both 15-LO expression and Treg cell number in a mouse model of LD. These results provide evidence that lymphatic 15-LO may represent a therapeutic target for LD by serving as a mediator of Treg cell populations to resolve inflammation.
    DOI:  https://doi.org/10.1038/s41467-023-43554-y
  43. Nat Commun. 2024 Jan 02. 15(1): 145
    Innate immune and proinflammatory signals activate the Hippo pathway via a Tak1-STRIPAK-Tao axis.
    Yinan Yang, Huijing Zhou, Xiawei Huang, Chengfang Wu, Kewei Zheng, Jingrong Deng, Yonggang Zheng, Jiahui Wang, Xiaofeng Chi, Xianjue Ma, Huimin Pan, Rui Shen, Duojia Pan, Bo Liu.
      The Hippo pathway controls developmental, homeostatic and regenerative tissue growth, and is frequently dysregulated in various diseases. Although this pathway can be activated by innate immune/inflammatory stimuli, the underlying mechanism is not fully understood. Here, we identify a conserved signaling cascade that leads to Hippo pathway activation by innate immune/inflammatory signals. We show that Tak1, a key kinase in innate immune/inflammatory signaling, activates the Hippo pathway by inducing the lysosomal degradation of Cka, an essential subunit of the STRIPAK PP2A complex that suppresses Hippo signaling. Suppression of STRIPAK results in the activation of Hippo pathway through Tao-Hpo signaling. We further show that Tak1-mediated Hippo signaling is involved in processes ranging from cell death to phagocytosis and innate immune memory. Our findings thus reveal a molecular connection between innate immune/inflammatory signaling and the evolutionally conserved Hippo pathway, thus contributing to our understanding of infectious, inflammatory and malignant diseases.
    DOI:  https://doi.org/10.1038/s41467-023-44542-y
  44. EMBO Rep. 2023 Dec 14.
    MTCH2 cooperates with MFN2 and lysophosphatidic acid synthesis to sustain mitochondrial fusion.
    Andres Goldman, Michael Mullokandov, Yehudit Zaltsman, Limor Regev, Smadar Levin-Zaidman, Atan Gross.
      Fusion of the outer mitochondrial membrane (OMM) is regulated by mitofusin 1 (MFN1) and 2 (MFN2), yet the differential contribution of each of these proteins is less understood. Mitochondrial carrier homolog 2 (MTCH2) also plays a role in mitochondrial fusion, but its exact function remains unresolved. MTCH2 overexpression enforces MFN2-independent mitochondrial fusion, proposedly by modulating the phospholipid lysophosphatidic acid (LPA), which is synthesized by glycerol-phosphate acyl transferases (GPATs) in the endoplasmic reticulum (ER) and the OMM. Here we report that MTCH2 requires MFN1 to enforce mitochondrial fusion and that fragmentation caused by loss of MTCH2 can be specifically counterbalanced by overexpression of MFN2 but not MFN1, partially independent of its GTPase activity and mitochondrial localization. Pharmacological inhibition of GPATs (GPATi) or silencing ER-resident GPATs suppresses MFN2's ability to compensate for the loss of MTCH2. Loss of either MTCH2, MFN2, or GPATi does not impair stress-induced mitochondrial fusion, whereas the combined loss of MTCH2 and GPATi or the combined loss of MTCH2 and MFN2 does. Taken together, we unmask two cooperative mechanisms that sustain mitochondrial fusion.
    Keywords:  LPA; MFN2; MTCH2; Mitochondria-ER Communication; Mitochondrial Fusion
    DOI:  https://doi.org/10.1038/s44319-023-00009-1
  45. Nat Comput Sci. 2023 May;3(5): 403-417
    The high-dimensional space of human diseases built from diagnosis records and mapped to genetic loci.
    Gengjie Jia, Yu Li, Xue Zhong, Kanix Wang, Milton Pividori, Rabab Alomairy, Aniello Esposito, Hatem Ltaief, Chikashi Terao, Masato Akiyama, Koichi Matsuda, David E Keyes, Hae Kyung Im, Takashi Gojobori, Yoichiro Kamatani, Michiaki Kubo, Nancy J Cox, James Evans, Xin Gao, Andrey Rzhetsky.
      Human diseases are traditionally studied as singular, independent entities, limiting researchers' capacity to view human illnesses as dependent states in a complex, homeostatic system. Here, using time-stamped clinical records of over 151 million unique Americans, we construct a disease representation as points in a continuous, high-dimensional space, where diseases with similar etiology and manifestations lie near one another. We use the UK Biobank cohort, with half a million participants, to perform a genome-wide association study of newly defined human quantitative traits reflecting individuals' health states, corresponding to patient positions in our disease space. We discover 116 genetic associations involving 108 genetic loci and then use ten disease constellations resulting from clustering analysis of diseases in the embedding space, as well as 30 common diseases, to demonstrate that these genetic associations can be used to robustly predict various morbidities.
    DOI:  https://doi.org/10.1038/s43588-023-00453-y
  46. Nat Commun. 2024 Jan 02. 15(1): 163
    MCT1-governed pyruvate metabolism is essential for antibody class-switch recombination through H3K27 acetylation.
    Wenna Chi, Na Kang, Linlin Sheng, Sichen Liu, Lei Tao, Xizhi Cao, Ye Liu, Can Zhu, Yuming Zhang, Bolong Wu, Ruiqun Chen, Lili Cheng, Jing Wang, Xiaolin Sun, Xiaohui Liu, Haiteng Deng, Jinliang Yang, Zhanguo Li, Wanli Liu, Ligong Chen.
      Monocarboxylate transporter 1 (MCT1) exhibits essential roles in cellular metabolism and energy supply. Although MCT1 is highly expressed in activated B cells, it is not clear how MCT1-governed monocarboxylates transportation is functionally coupled to antibody production during the glucose metabolism. Here, we report that B cell-lineage deficiency of MCT1 significantly influences the class-switch recombination (CSR), rendering impaired IgG antibody responses in Mct1f/fMb1Cre mice after immunization. Metabolic flux reveals that glucose metabolism is significantly reprogrammed from glycolysis to oxidative phosphorylation in Mct1-deficient B cells upon activation. Consistently, activation-induced cytidine deaminase (AID), is severely suppressed in Mct1-deficient B cells due to the decreased level of pyruvate metabolite. Mechanistically, MCT1 is required to maintain the optimal concentration of pyruvate to secure the sufficient acetylation of H3K27 for the elevated transcription of AID in activated B cells. Clinically, we found that MCT1 expression levels are significantly upregulated in systemic lupus erythematosus patients, and Mct1 deficiency can alleviate the symptoms of bm12-induced murine lupus model. Collectively, these results demonstrate that MCT1-mediated pyruvate metabolism is required for IgG antibody CSR through an epigenetic dependent AID transcription, revealing MCT1 as a potential target for vaccine development and SLE disease treatment.
    DOI:  https://doi.org/10.1038/s41467-023-44540-0
  47. Nat Biotechnol. 2024 Jan 02.
    IL-10-expressing CAR T cells resist dysfunction and mediate durable clearance of solid tumors and metastases.
    Yang Zhao, Jiangqing Chen, Massimo Andreatta, Bing Feng, Yu-Qing Xie, Mathias Wenes, Yi Wang, Min Gao, Xiaomeng Hu, Pedro Romero, Santiago Carmona, Jie Sun, Yugang Guo, Li Tang.
      The success of chimeric antigen receptor (CAR) T cell therapy in treating several hematopoietic malignancies has been difficult to replicate in solid tumors, in part because of T cell exhaustion and eventually dysfunction. To counter T cell dysfunction in the tumor microenvironment, we metabolically armored CAR T cells by engineering them to secrete interleukin-10 (IL-10). We show that IL-10 CAR T cells preserve intact mitochondrial structure and function in the tumor microenvironment and increase oxidative phosphorylation in a mitochondrial pyruvate carrier-dependent manner. IL-10 secretion promoted proliferation and effector function of CAR T cells, leading to complete regression of established solid tumors and metastatic cancers across several cancer types in syngeneic and xenograft mouse models, including colon cancer, breast cancer, melanoma and pancreatic cancer. IL-10 CAR T cells also induced stem cell-like memory responses in lymphoid organs that imparted durable protection against tumor rechallenge. Our results establish a generalizable approach to counter CAR T cell dysfunction through metabolic armoring, leading to solid tumor eradication and long-lasting immune protection.
    DOI:  https://doi.org/10.1038/s41587-023-02060-8
  48. Science. 2024 Jan 05. 383(6678): 21
    Nuclear disasters-in-waiting.
    Richard Stone.
      
    DOI:  https://doi.org/10.1126/science.adn7987
  49. Nat Commun. 2024 Jan 02. 15(1): 168
    Mic19 depletion impairs endoplasmic reticulum-mitochondrial contacts and mitochondrial lipid metabolism and triggers liver disease.
    Jun Dong, Li Chen, Fei Ye, Junhui Tang, Bing Liu, Jiacheng Lin, Pang-Hu Zhou, Bin Lu, Min Wu, Jia-Hong Lu, Jing-Jing He, Simone Engelender, Qingtao Meng, Zhiyin Song, He He.
      Endoplasmic reticulum (ER)-mitochondria contacts are critical for the regulation of lipid transport, synthesis, and metabolism. However, the molecular mechanism and physiological function of endoplasmic reticulum-mitochondrial contacts remain unclear. Here, we show that Mic19, a key subunit of MICOS (mitochondrial contact site and cristae organizing system) complex, regulates ER-mitochondria contacts by the EMC2-SLC25A46-Mic19 axis. Mic19 liver specific knockout (LKO) leads to the reduction of ER-mitochondrial contacts, mitochondrial lipid metabolism disorder, disorganization of mitochondrial cristae and mitochondrial unfolded protein stress response in mouse hepatocytes, impairing liver mitochondrial fatty acid β-oxidation and lipid metabolism, which may spontaneously trigger nonalcoholic steatohepatitis (NASH) and liver fibrosis in mice. Whereas, the re-expression of Mic19 in Mic19 LKO hepatocytes blocks the development of liver disease in mice. In addition, Mic19 overexpression suppresses MCD-induced fatty liver disease. Thus, our findings uncover the EMC2-SLC25A46-Mic19 axis as a pathway regulating ER-mitochondria contacts, and reveal that impairment of ER-mitochondria contacts may be a mechanism associated with the development of NASH and liver fibrosis.
    DOI:  https://doi.org/10.1038/s41467-023-44057-6
  50. BMC Genomics. 2024 Jan 02. 25(1): 5
    Ribosomal profiling of human endogenous retroviruses in healthy tissues.
    Nicholas Dopkins, Bhavya Singh, Stephanie Michael, Panpan Zhang, Jez L Marston, Tongyi Fei, Manvendra Singh, Cedric Feschotte, Nicholas Collins, Matthew L Bendall, Douglas F Nixon.
      Human endogenous retroviruses (HERVs) are the germline embedded proviral fragments of ancient retroviral infections that make up roughly 8% of the human genome. Our understanding of HERVs in physiology primarily surrounds their non-coding functions, while their protein coding capacity remains virtually uncharacterized. Therefore, we applied the bioinformatic pipeline "hervQuant" to high-resolution ribosomal profiling of healthy tissues to provide a comprehensive overview of translationally active HERVs. We find that HERVs account for 0.1-0.4% of all translation in distinct tissue-specific profiles. Collectively, our study further supports claims that HERVs are actively translated throughout healthy tissues to provide sequences of retroviral origin to the human proteome.
    Keywords:  Dark genome; Endoretrotranslatome (ERT); Human endogenous retrovirus (HERV); Protein translation; Ribosomal profiling (RiboSeq)
    DOI:  https://doi.org/10.1186/s12864-023-09909-x
  51. Nat Commun. 2024 Jan 03. 15(1): 236
    The polyketide to fatty acid transition in the evolution of animal lipid metabolism.
    Zhenjian Lin, Feng Li, Patrick J Krug, Eric W Schmidt.
      Animals synthesize simple lipids using a distinct fatty acid synthase (FAS) related to the type I polyketide synthase (PKS) enzymes that produce complex specialized metabolites. The evolutionary origin of the animal FAS and its relationship to the diversity of PKSs remain unclear despite the critical role of lipid synthesis in cellular metabolism. Recently, an animal FAS-like PKS (AFPK) was identified in sacoglossan molluscs. Here, we explore the phylogenetic distribution of AFPKs and other PKS and FAS enzymes across the tree of life. We found AFPKs widely distributed in arthropods and molluscs (>6300 newly described AFPK sequences). The AFPKs form a clade with the animal FAS, providing an evolutionary link bridging the type I PKSs and the animal FAS. We found molluscan AFPK diversification correlated with shell loss, suggesting AFPKs provide a chemical defense. Arthropods have few or no PKSs, but our results indicate AFPKs contributed to their ecological and evolutionary success by facilitating branched hydrocarbon and pheromone biosynthesis. Although animal metabolism is well studied, surprising new metabolic enzyme classes such as AFPKs await discovery.
    DOI:  https://doi.org/10.1038/s41467-023-44497-0
  52. Nat Cell Biol. 2024 Jan 02.
    Gut microbial metabolite facilitates colorectal cancer development via ferroptosis inhibition.
    Weiwei Cui, Meng Guo, Dong Liu, Peng Xiao, Chuancheng Yang, Haidi Huang, Chunhui Liang, Yinghong Yang, Xiaolong Fu, Yudan Zhang, Jiaxing Liu, Shuang Shi, Jingjing Cong, Zili Han, Yunfei Xu, Lutao Du, Chengqian Yin, Yongchun Zhang, Jinpeng Sun, Wei Gu, Renjie Chai, Shu Zhu, Bo Chu.
      The gut microbiota play a pivotal role in human health. Emerging evidence indicates that gut microbes participate in the progression of tumorigenesis through the generation of carcinogenic metabolites. However, the underlying molecular mechanism is largely unknown. In the present study we show that a tryptophan metabolite derived from Peptostreptococcus anaerobius, trans-3-indoleacrylic acid (IDA), facilitates colorectal carcinogenesis. Mechanistically, IDA acts as an endogenous ligand of an aryl hydrocarbon receptor (AHR) to transcriptionally upregulate the expression of ALDH1A3 (aldehyde dehydrogenase 1 family member A3), which utilizes retinal as a substrate to generate NADH, essential for ferroptosis-suppressor protein 1(FSP1)-mediated synthesis of reduced coenzyme Q10. Loss of AHR or ALDH1A3 largely abrogates IDA-promoted tumour development both in vitro and in vivo. It is interesting that P. anaerobius is significantly enriched in patients with colorectal cancer (CRC). IDA treatment or implantation of P. anaerobius promotes CRC progression in both xenograft model and ApcMin/+ mice. Together, our findings demonstrate that targeting the IDA-AHR-ALDH1A3 axis should be promising for ferroptosis-related CRC treatment.
    DOI:  https://doi.org/10.1038/s41556-023-01314-6
  53. Commun Biol. 2024 Jan 02. 7(1): 8
    Cholesterol modulates type I/II TGF-β receptor complexes and alters the balance between Smad and Akt signaling in hepatocytes.
    Roohi Chaudhary, Laureen S Goodman, Sai Wang, Anastasia Asimakopoulos, Ralf Weiskirchen, Steven Dooley, Marcelo Ehrlich, Yoav I Henis.
      Cholesterol mediates membrane compartmentalization, affecting signaling via differential distribution of receptors and signaling mediators. While excessive cholesterol and aberrant transforming growth factor-β (TGF-β) signaling characterize multiple liver diseases, their linkage to canonical vs. non-canonical TGF-β signaling remained unclear. Here, we subjected murine hepatocytes to cholesterol depletion (CD) or enrichment (CE), followed by biophysical studies on TGF-β receptor heterocomplex formation, and output to Smad2/3 vs. Akt pathways. Prior to ligand addition, raft-dependent preformed heteromeric receptor complexes were observed. Smad2/3 phosphorylation persisted following CD or CE. CD enhanced phospho-Akt (pAkt) formation by TGF-β or epidermal growth factor (EGF) at 5 min, while reducing it at later time points. Conversely, pAkt formation by TGF-β or EGF was inhibited by CE, suggesting a direct effect on the Akt pathway. The modulation of the balance between TGF-β signaling to Smad2/3 vs. pAkt (by TGF-β or EGF) has potential implications for hepatic diseases and malignancies.
    DOI:  https://doi.org/10.1038/s42003-023-05654-9
  54. Nat Commun. 2024 Jan 02. 15(1): 122
    FOXP3+ regulatory T cell perturbation mediated by the IFNγ-STAT1-IFITM3 feedback loop is essential for anti-tumor immunity.
    Xinnan Liu, Weiqi Zhang, Yichao Han, Hao Cheng, Qi Liu, Shouyu Ke, Fangming Zhu, Ying Lu, Xin Dai, Chuan Wang, Gonghua Huang, Bing Su, Qiang Zou, Huabing Li, Wenyi Zhao, Lianbo Xiao, Linrong Lu, Xuemei Tong, Fan Pan, Hecheng Li, Bin Li.
      Targeting tumor-infiltrating regulatory T cells (Tregs) is an efficient way to evoke an anti-tumor immune response. However, how Tregs maintain their fragility and stability remains largely unknown. IFITM3 and STAT1 are interferon-induced genes that play a positive role in the progression of tumors. Here, we showed that IFITM3-deficient Tregs blunted tumor growth by strengthening the tumor-killing response and displayed the Th1-like Treg phenotype with higher secretion of IFNγ. Mechanistically, depletion of IFITM3 enhances the translation and phosphorylation of STAT1. On the contrary, the decreased IFITM3 expression in STAT1-deficient Tregs indicates that STAT1 conversely regulates the expression of IFITM3 to form a feedback loop. Blocking the inflammatory cytokine IFNγ or directly depleting STAT1-IFITM3 axis phenocopies the restored suppressive function of tumor-infiltrating Tregs in the tumor model. Overall, our study demonstrates that the perturbation of tumor-infiltrating Tregs through the IFNγ-IFITM3-STAT1 feedback loop is essential for anti-tumor immunity and constitutes a targetable vulnerability of cancer immunotherapy.
    DOI:  https://doi.org/10.1038/s41467-023-44391-9
  55. Nat Cell Biol. 2024 Jan 04.
    FOXO1-mediated lipid metabolism maintains mammalian embryos in dormancy.
    Vera A van der Weijden, Maximilian Stötzel, Dhanur P Iyer, Beatrix Fauler, Elzbieta Gralinska, Mohammed Shahraz, David Meierhofer, Martin Vingron, Steffen Rulands, Theodore Alexandrov, Thorsten Mielke, Aydan Bulut-Karslioglu.
      Mammalian developmental timing is adjustable in vivo by preserving pre-implantation embryos in a dormant state called diapause. Inhibition of the growth regulator mTOR (mTORi) pauses mouse development in vitro, yet how embryonic dormancy is maintained is not known. Here we show that mouse embryos in diapause are sustained by using lipids as primary energy source. In vitro, supplementation of embryos with the metabolite L-carnitine balances lipid consumption, puts the embryos in deeper dormancy and boosts embryo longevity. We identify FOXO1 as an essential regulator of the energy balance in dormant embryos and propose, through meta-analyses of dormant cell signatures, that it may be a common regulator of dormancy across adult tissues. Our results lift a constraint on in vitro embryo survival and suggest that lipid metabolism may be a critical metabolic transition relevant for longevity and stem cell function across tissues.
    DOI:  https://doi.org/10.1038/s41556-023-01325-3
  56. Nat Commun. 2024 Jan 05. 15(1): 324
    Secreted IgM modulates IL-10 expression in B cells.
    Shannon Eileen McGettigan, Lazaro Emilio Aira, Gaurav Kumar, Romain Ballet, Eugene C Butcher, Nicole Baumgarth, Gudrun F Debes.
      IL-10+ B cells are critical for immune homeostasis and restraining immune responses in infection, cancer, and inflammation; however, the signals that govern IL-10+ B cell differentiation are ill-defined. Here we find that IL-10+ B cells expand in mice lacking secreted IgM ((s)IgM-/-) up to 10-fold relative to wildtype (WT) among all major B cell and regulatory B cell subsets. The IL-10+ B cell increase is polyclonal and presents within 24 hours of birth. In WT mice, sIgM is produced prenatally and limits the expansion of IL-10+ B cells. Lack of the high affinity receptor for sIgM, FcμR, in B cells translates into an intermediate IL-10+ B cell phenotype relative to WT or sIgM-/- mice. Our study thus shows that sIgM regulates IL-10 programming in B cells in part via B cell-expressed FcμR, thereby revealing a function of sIgM in regulating immune homeostasis.
    DOI:  https://doi.org/10.1038/s41467-023-44382-w
  57. Nat Commun. 2024 Jan 04. 15(1): 265
    Oligodendrocyte calcium signaling promotes actin-dependent myelin sheath extension.
    Manasi Iyer, Husniye Kantarci, Madeline H Cooper, Nicholas Ambiel, Sammy Weiser Novak, Leonardo R Andrade, Mable Lam, Graham Jones, Alexandra E Münch, Xinzhu Yu, Baljit S Khakh, Uri Manor, J Bradley Zuchero.
      Myelin is essential for rapid nerve signaling and is increasingly found to play important roles in learning and in diverse diseases of the CNS. Morphological parameters of myelin such as sheath length are thought to precisely tune conduction velocity, but the mechanisms controlling sheath morphology are poorly understood. Local calcium signaling has been observed in nascent myelin sheaths and can be modulated by neuronal activity. However, the role of calcium signaling in sheath formation remains incompletely understood. Here, we use genetic tools to attenuate oligodendrocyte calcium signaling during myelination in the developing mouse CNS. Surprisingly, genetic calcium attenuation does not grossly affect the number of myelinated axons or myelin thickness. Instead, calcium attenuation causes myelination defects resulting in shorter, dysmorphic sheaths. Mechanistically, calcium attenuation reduces actin filaments in oligodendrocytes, and an intact actin cytoskeleton is necessary and sufficient to achieve accurate myelin morphology. Together, our work reveals a cellular mechanism required for accurate CNS myelin formation and may provide mechanistic insight into how oligodendrocytes respond to neuronal activity to sculpt and refine myelin sheaths.
    DOI:  https://doi.org/10.1038/s41467-023-44238-3
  58. Nat Commun. 2024 Jan 03. 15(1): 233
    A natural biogenic nanozyme for scavenging superoxide radicals.
    Long Ma, Jia-Jia Zheng, Ning Zhou, Ruofei Zhang, Long Fang, Yili Yang, Xingfa Gao, Chunying Chen, Xiyun Yan, Kelong Fan.
      Biominerals, the inorganic minerals of organisms, are known mainly for their physical property-related functions in modern living organisms. Our recent discovery of the enzyme-like activities of nanomaterials, coined as nanozyme, inspires the hypothesis that nano-biominerals might function as enzyme-like catalyzers in cells. Here we report that the iron cores of biogenic ferritins act as natural nanozymes to scavenge superoxide radicals. Through analyzing eighteen representative ferritins from three living kingdoms, we find that the iron core of prokaryote ferritin possesses higher superoxide-diminishing activity than that of eukaryotes. Further investigation reveals that the differences in catalytic capability result from the iron/phosphate ratio changes in the iron core, which is mainly determined by the structures of ferritins. The phosphate in the iron core switches the iron core from single crystalline to amorphous iron phosphate-like structure, resulting in decreased affinity to the hydrogen proton of the ferrihydrite-like core that facilitates its reaction with superoxide in a manner different from that of ferric ions. Furthermore, overexpression of ferritins with high superoxide-diminishing activities in E. coli increases the resistance to superoxide, whereas bacterioferritin knockout or human ferritin knock-in diminishes free radical tolerance, highlighting the physiological antioxidant role of this type of nanozymes.
    DOI:  https://doi.org/10.1038/s41467-023-44463-w
  59. Nat Aging. 2024 Jan 04.
    Beyond integrated care for older adults.
    John R Beard.
      
    DOI:  https://doi.org/10.1038/s43587-023-00542-7
  60. Nat Commun. 2024 Jan 02. 15(1): 180
    Mutant p53 gains oncogenic functions through a chromosomal instability-induced cytosolic DNA response.
    Mei Zhao, Tianxiao Wang, Frederico O Gleber-Netto, Zhen Chen, Daniel J McGrail, Javier A Gomez, Wutong Ju, Mayur A Gadhikar, Wencai Ma, Li Shen, Qi Wang, Ximing Tang, Sen Pathak, Maria Gabriela Raso, Jared K Burks, Shiaw-Yih Lin, Jing Wang, Asha S Multani, Curtis R Pickering, Junjie Chen, Jeffrey N Myers, Ge Zhou.
      Inactivating TP53 mutations leads to a loss of function of p53, but can also often result in oncogenic gain-of-function (GOF) of mutant p53 (mutp53) proteins which promotes tumor development and progression. The GOF activities of TP53 mutations are well documented, but the mechanisms involved remain poorly understood. Here, we study the mutp53 interactome and find that by targeting minichromosome maintenance complex components (MCMs), GOF mutp53 predisposes cells to replication stress and chromosomal instability (CIN), leading to a tumor cell-autonomous and cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING)-dependent cytosolic DNA response that activates downstream non-canonical nuclear factor kappa light chain enhancer of activated B cell (NC-NF-κB) signaling. Consequently, GOF mutp53-MCMs-CIN-cytosolic DNA-cGAS-STING-NC-NF-κB signaling promotes tumor cell metastasis and an immunosuppressive tumor microenvironment through antagonizing interferon signaling and regulating genes associated with pro-tumorigenic inflammation. Our findings have important implications for understanding not only the GOF activities of TP53 mutations but also the genome-guardian role of p53 and its inactivation during tumor development and progression.
    DOI:  https://doi.org/10.1038/s41467-023-44239-2
  61. Proc Natl Acad Sci U S A. 2024 Jan 09. 121(2): e2316104121
    A TLR4/TRAF6-dependent signaling pathway mediates NCoR coactivator complex formation for inflammatory gene activation.
    Yohei Abe, Eric R Kofman, Zhengyu Ouyang, Grisel Cruz-Becerra, Nathanael J Spann, Jason S Seidman, Ty D Troutman, Joshua D Stender, Havilah Taylor, Weiwei Fan, Verena M Link, Zeyang Shen, Juro Sakai, Michael Downes, Ronald M Evans, James T Kadonaga, Michael G Rosenfeld, Christopher K Glass.
      The nuclear receptor corepressor (NCoR) forms a complex with histone deacetylase 3 (HDAC3) that mediates repressive functions of unliganded nuclear receptors and other transcriptional repressors by deacetylation of histone substrates. Recent studies provide evidence that NCoR/HDAC3 complexes can also exert coactivator functions in brown adipocytes by deacetylating and activating PPARγ coactivator 1α (PGC1α) and that signaling via receptor activator of nuclear factor kappa-B (RANK) promotes the formation of a stable NCoR/HDAC3/PGC1β complex that coactivates nuclear factor kappa-B (NFκB)- and activator protein 1 (AP-1)-dependent genes required for osteoclast differentiation. Here, we demonstrate that activation of Toll-like receptor (TLR) 4, but not TLR3, the interleukin 4 (IL4) receptor nor the Type I interferon receptor, also promotes assembly of an NCoR/HDAC3/PGC1β coactivator complex. Receptor-specific utilization of TNF receptor-associated factor 6 (TRAF6) and downstream activation of extracellular signal-regulated kinase 1 (ERK1) and TANK-binding kinase 1 (TBK1) accounts for the common ability of RANK and TLR4 to drive assembly of an NCoR/HDAC3/PGC1β complex in macrophages. ERK1, the p65 component of NFκB, and the p300 histone acetyltransferase (HAT) are also components of the induced complex and are associated with local histone acetylation and transcriptional activation of TLR4-dependent enhancers and promoters. These observations identify a TLR4/TRAF6-dependent signaling pathway that converts NCoR from a corepressor of nuclear receptors to a coactivator of NFκB and AP-1 that may be relevant to functions of NCoR in other developmental and homeostatic processes.
    Keywords:  NCoR; PGC1β; TLR4; TRAF6; macrophage
    DOI:  https://doi.org/10.1073/pnas.2316104121
  62. Nat Commun. 2024 Jan 02. 15(1): 28
    MAPS: pathologist-level cell type annotation from tissue images through machine learning.
    Muhammad Shaban, Yunhao Bai, Huaying Qiu, Shulin Mao, Jason Yeung, Yao Yu Yeo, Vignesh Shanmugam, Han Chen, Bokai Zhu, Jason L Weirather, Garry P Nolan, Margaret A Shipp, Scott J Rodig, Sizun Jiang, Faisal Mahmood.
      Highly multiplexed protein imaging is emerging as a potent technique for analyzing protein distribution within cells and tissues in their native context. However, existing cell annotation methods utilizing high-plex spatial proteomics data are resource intensive and necessitate iterative expert input, thereby constraining their scalability and practicality for extensive datasets. We introduce MAPS (Machine learning for Analysis of Proteomics in Spatial biology), a machine learning approach facilitating rapid and precise cell type identification with human-level accuracy from spatial proteomics data. Validated on multiple in-house and publicly available MIBI and CODEX datasets, MAPS outperforms current annotation techniques in terms of speed and accuracy, achieving pathologist-level precision even for typically challenging cell types, including tumor cells of immune origin. By democratizing rapidly deployable and scalable machine learning annotation, MAPS holds significant potential to expedite advances in tissue biology and disease comprehension.
    DOI:  https://doi.org/10.1038/s41467-023-44188-w
  63. Nat Biotechnol. 2024 Jan 02.
    Inferring super-resolution tissue architecture by integrating spatial transcriptomics with histology.
    Daiwei Zhang, Amelia Schroeder, Hanying Yan, Haochen Yang, Jian Hu, Michelle Y Y Lee, Kyung S Cho, Katalin Susztak, George X Xu, Michael D Feldman, Edward B Lee, Emma E Furth, Linghua Wang, Mingyao Li.
      Spatial transcriptomics (ST) has demonstrated enormous potential for generating intricate molecular maps of cells within tissues. Here we present iStar, a method based on hierarchical image feature extraction that integrates ST data and high-resolution histology images to predict spatial gene expression with super-resolution. Our method enhances gene expression resolution to near-single-cell levels in ST and enables gene expression prediction in tissue sections where only histology images are available.
    DOI:  https://doi.org/10.1038/s41587-023-02019-9
This page is being maintained by Thomas Krichel. It was last updated on 2024‒01‒14 at 6:03.