bims-nimamd Biomed News
on Neuroimmunity and neuroinflammation in ageing and metabolic disease
Issue of 2023–09–10
forty-six papers selected by
Fawaz Alzaïd, Sorbonne Université
  1. Finding my joy.
  2. Bacteroides Fragilis in the gut microbiomes of Alzheimer's disease activates microglia and triggers pathogenesis in neuronal C/EBPβ transgenic mice.
  3. Cold-activated brown fat-derived extracellular vesicle-miR-378a-3p stimulates hepatic gluconeogenesis in male mice.
  4. CXCR6 orchestrates brain CD8+ T cell residency and limits mouse Alzheimer's disease pathology.
  5. The YAP-TEAD complex promotes senescent cell survival by lowering endoplasmic reticulum stress.
  6. A platelet-derived factor protects the ageing brain.
  7. Symmetric inheritance of parental histones governs epigenome maintenance and embryonic stem cell identity.
  8. MaxFuse enables data integration across weakly linked spatial and single-cell modalities.
  9. CD8+ T cells pump the brakes on Alzheimer's disease.
  10. TAZ2 truncation confers overactivation of p300 and cellular vulnerability to HDAC inhibition.
  11. MKP1 promotes nonalcoholic steatohepatitis by suppressing AMPK activity through LKB1 nuclear retention.
  12. A type 2 immune circuit in the stomach controls mammalian adaptation to dietary chitin.
  13. Structures of liganded glycosylphosphatidylinositol transamidase illuminate GPI-AP biogenesis.
  14. GWAS of random glucose in 476,326 individuals provide insights into diabetes pathophysiology, complications and treatment stratification.
  15. Multifaceted membrane interactions of human Atg3 promote LC3-phosphatidylethanolamine conjugation during autophagy.
  16. NAD(H) homeostasis underlies host protection mediated by glycolytic myeloid cells in tuberculosis.
  17. Thymic mimetic cells function beyond self-tolerance.
  18. eIF3d controls the persistent integrated stress response.
  19. Time-dependent cell-state selection identifies transiently expressed genes regulating ILC2 activation.
  20. Metabolic and functional remodeling of colonic macrophages in response to high-fat diet-induced obesity.
  21. Mitochondrial leak metabolism induces the Spemann-Mangold Organizer via Hif-1α in Xenopus.
  22. Symmetric inheritance of parental histones contributes to safeguarding the fate of mouse embryonic stem cells during differentiation.
  23. A super-enhancer-regulated RNA-binding protein cascade drives pancreatic cancer.
  24. Neutrophil metalloproteinase driven spleen damage hampers infection control of trypanosomiasis.
  25. Orally delivered lactate-producing bacteria limit CNS autoimmunity.
  26. Shared and distinct genetic etiologies for different types of clonal hematopoiesis.
  27. The complex relationship between cell transcriptomic state and phenotype.
  28. Damaged mitochondria recruit the effector NEMO to activate NF-κB signaling.
  29. Epigenetic inheritance is unfaithful at intermediately methylated CpG sites.
  30. A cytotoxic T cell inspired oncolytic nanosystem promotes lytic cell death by lipid peroxidation and elicits antitumor immune responses.
  31. Ascl1 and Ngn2 convert mouse embryonic stem cells to neurons via functionally distinct paths.
  32. CD44 connects autophagy decline and ageing in the vascular endothelium.
  33. A tissue-intrinsic IL-33/EGF circuit promotes epithelial regeneration after intestinal injury.
  34. Hyodeoxycholic acid ameliorates nonalcoholic fatty liver disease by inhibiting RAN-mediated PPARα nucleus-cytoplasm shuttling.
  35. The obesity-linked human lncRNA AATBC stimulates mitochondrial function in adipocytes.
  36. Polθ is phosphorylated by PLK1 to repair double-strand breaks in mitosis.
  37. Genetic variants of phospholipase C-γ2 alter the phenotype and function of microglia and confer differential risk for Alzheimer's disease.
  38. Infection-experienced HSPCs protect against infections by generating neutrophils with enhanced mitochondrial bactericidal activity.
  39. Direct observation of tRNA-chaperoned folding of a dynamic mRNA ensemble.
  40. Design principles for cyclin K molecular glue degraders.
  41. Plant immunity suppression by an exo-β-1,3-glucanase and an elongation factor 1α of the rice blast fungus.
  42. Deciphering early human pancreas development at the single-cell level.
  43. Regulation with cell size ensures mitochondrial DNA homeostasis during cell growth.
  44. Alleviating symptoms of neurodegenerative disorders by astrocyte-specific overexpression of TMEM164 in mice.
  45. Serotonin signaling regulates actomyosin contractility during morphogenesis in evolutionarily divergent lineages.
  46. Stem-like CD4+ T cells in perivascular tertiary lymphoid structures sustain autoimmune vasculitis.
  1. Science. 2023 Sep 08. 381(6662): 1126
    Finding my joy.
    Megan Keller.
      
    DOI:  https://doi.org/10.1126/science.adk6158
  2. Nat Commun. 2023 Sep 06. 14(1): 5471
    Bacteroides Fragilis in the gut microbiomes of Alzheimer's disease activates microglia and triggers pathogenesis in neuronal C/EBPβ transgenic mice.
    Yiyuan Xia, Yifan Xiao, Zhi-Hao Wang, Xia Liu, Ashfaqul M Alam, John P Haran, Beth A McCormick, Xiji Shu, Xiaochuan Wang, Keqiang Ye.
      Gut dysbiosis contributes to Alzheimer's disease (AD) pathogenesis, and Bacteroides strains are selectively elevated in AD gut microbiota. However, it remains unknown which Bacteroides species and how their metabolites trigger AD pathologies. Here we show that Bacteroides fragilis and their metabolites 12-hydroxy-heptadecatrienoic acid (12-HHTrE) and Prostaglandin E2 (PGE2) activate microglia and induce AD pathogenesis in neuronal C/EBPβ transgenic mice. Recolonization of antibiotics cocktail-pretreated Thy1-C/EBPβ transgenic mice with AD patient fecal samples elicits AD pathologies, associated with C/EBPβ/Asparaginyl endopeptidase (AEP) pathway upregulation, microglia activation, and cognitive disorders compared to mice receiving healthy donors' fecal microbiota transplantation (FMT). Microbial 16S rRNA sequencing analysis shows higher abundance of proinflammatory Bacteroides fragilis in AD-FMT mice. Active components characterization from the sera and brains of the transplanted mice revealed that both 12-HHTrE and PGE2 activate primary microglia, fitting with poly-unsaturated fatty acid (PUFA) metabolites enrichment identified by metabolomics. Strikingly, recolonization with live but not dead Bacteroides fragilis elicited AD pathologies in Thy1-C/EBPβ transgenic mice, so did 12-HHTrE or PGE2 treatment alone. Collectively, our findings support a causal role for Bacteroides fragilis and the PUFA metabolites in activating microglia and inducing AD pathologies in Thy1- C/EBPβ transgenic mice.
    DOI:  https://doi.org/10.1038/s41467-023-41283-w
  3. Nat Commun. 2023 Sep 06. 14(1): 5480
    Cold-activated brown fat-derived extracellular vesicle-miR-378a-3p stimulates hepatic gluconeogenesis in male mice.
    Jinhong Xu, Le Cui, Jiaqi Wang, Shasha Zheng, Huahua Zhang, Shuo Ke, Xiaoqin Cao, Yanteng Shi, Jing Li, Ke Zen, Antonio Vidal-Puig, Chen-Yu Zhang, Liang Li, Xiaohong Jiang.
      During cold exposure, activated brown adipose tissue (BAT) takes up a large amount of circulating glucose to fuel non-shivering thermogenesis and defend against hypothermia. However, little is known about the endocrine function of BAT controlling glucose homoeostasis under this thermoregulatory challenge. Here, we show that in male mice, activated BAT-derived extracellular vesicles (BDEVs) reprogram systemic glucose metabolism by promoting hepatic gluconeogenesis during cold stress. Cold exposure facilitates the selective packaging of miR-378a-3p-one of the BAT-enriched miRNAs-into EVs and delivery into the liver. BAT-derived miR-378a-3p enhances gluconeogenesis by targeting p110α. miR-378 KO mice display reduced hepatic gluconeogenesis during cold exposure, while restoration of miR-378a-3p in iBAT induces the expression of gluconeogenic genes in the liver. These findings provide a mechanistic understanding of BDEV-miRNA as stress-induced batokine to coordinate systemic glucose homoeostasis. This miR-378a-3p-mediated interorgan communication highlights a novel endocrine function of BAT in preventing hypoglycemia during cold stress.
    DOI:  https://doi.org/10.1038/s41467-023-41160-6
  4. Nat Immunol. 2023 Sep 07.
    CXCR6 orchestrates brain CD8+ T cell residency and limits mouse Alzheimer's disease pathology.
    Wei Su, Jordy Saravia, Isabel Risch, Sherri Rankin, Cliff Guy, Nicole M Chapman, Hao Shi, Yu Sun, Anil Kc, Wei Li, Hongling Huang, Seon Ah Lim, Haoran Hu, Yan Wang, Danting Liu, Yun Jiao, Ping-Chung Chen, Hadeer Soliman, Koon-Kiu Yan, Jonathan Zhang, Peter Vogel, Xueyan Liu, Geidy E Serrano, Thomas G Beach, Jiyang Yu, Junmin Peng, Hongbo Chi.
      Neurodegenerative diseases, including Alzheimer's disease (AD), are characterized by innate immune-mediated inflammation, but functional and mechanistic effects of the adaptive immune system remain unclear. Here we identify brain-resident CD8+ T cells that coexpress CXCR6 and PD-1 and are in proximity to plaque-associated microglia in human and mouse AD brains. We also establish that CD8+ T cells restrict AD pathologies, including β-amyloid deposition and cognitive decline. Ligand-receptor interaction analysis identifies CXCL16-CXCR6 intercellular communication between microglia and CD8+ T cells. Further, Cxcr6 deficiency impairs accumulation, tissue residency programming and clonal expansion of brain PD-1+CD8+ T cells. Ablation of Cxcr6 or CD8+ T cells ultimately increases proinflammatory cytokine production from microglia, with CXCR6 orchestrating brain CD8+ T cell-microglia colocalization. Collectively, our study reveals protective roles for brain CD8+ T cells and CXCR6 in mouse AD pathogenesis and highlights that microenvironment-specific, intercellular communication orchestrates tissue homeostasis and protection from neuroinflammation.
    DOI:  https://doi.org/10.1038/s41590-023-01604-z
  5. Nat Aging. 2023 Sep 04.
    The YAP-TEAD complex promotes senescent cell survival by lowering endoplasmic reticulum stress.
    Carlos Anerillas, Krystyna Mazan-Mamczarz, Allison B Herman, Rachel Munk, Kwan-Wood Gabriel Lam, Miguel Calvo-Rubio, Amanda Garrido, Dimitrios Tsitsipatis, Jennifer L Martindale, Gisela Altés, Martina Rossi, Yulan Piao, Jinshui Fan, Chang-Yi Cui, Supriyo De, Kotb Abdelmohsen, Rafael de Cabo, Myriam Gorospe.
      Sublethal cell damage can trigger senescence, a complex adaptive program characterized by growth arrest, resistance to apoptosis and a senescence-associated secretory phenotype (SASP). Here, a whole-genome CRISPR knockout screen revealed that proteins in the YAP-TEAD pathway influenced senescent cell viability. Accordingly, treating senescent cells with a drug that inhibited this pathway, verteporfin (VPF), selectively triggered apoptotic cell death largely by derepressing DDIT4, which in turn inhibited mTOR. Reducing mTOR function in senescent cells diminished endoplasmic reticulum (ER) biogenesis, triggering ER stress and apoptosis due to high demands on ER function by the SASP. Importantly, VPF treatment decreased the numbers of senescent cells in the organs of old mice and mice exhibiting doxorubicin-induced senescence. Moreover, VPF treatment reduced immune cell infiltration and pro-fibrotic transforming growth factor-β signaling in aging mouse lungs, improving tissue homeostasis. We present an alternative senolytic strategy that eliminates senescent cells by hindering ER activity required for SASP production.
    DOI:  https://doi.org/10.1038/s43587-023-00480-4
  6. Nat Rev Immunol. 2023 Sep 04.
    A platelet-derived factor protects the ageing brain.
    Yvonne Bordon.
      
    DOI:  https://doi.org/10.1038/s41577-023-00939-w
  7. Nat Genet. 2023 Sep;55(9): 1567-1578
    Symmetric inheritance of parental histones governs epigenome maintenance and embryonic stem cell identity.
    Alice Wenger, Alva Biran, Nicolas Alcaraz, Alba Redó-Riveiro, Annika Charlotte Sell, Robert Krautz, Valentin Flury, Nazaret Reverón-Gómez, Victor Solis-Mezarino, Moritz Völker-Albert, Axel Imhof, Robin Andersson, Joshua M Brickman, Anja Groth.
      Modified parental histones are segregated symmetrically to daughter DNA strands during replication and can be inherited through mitosis. How this may sustain the epigenome and cell identity remains unknown. Here we show that transmission of histone-based information during DNA replication maintains epigenome fidelity and embryonic stem cell plasticity. Asymmetric segregation of parental histones H3-H4 in MCM2-2A mutants compromised mitotic inheritance of histone modifications and globally altered the epigenome. This included widespread spurious deposition of repressive modifications, suggesting elevated epigenetic noise. Moreover, H3K9me3 loss at repeats caused derepression and H3K27me3 redistribution across bivalent promoters correlated with misexpression of developmental genes. MCM2-2A mutation challenged dynamic transitions in cellular states across the cell cycle, enhancing naïve pluripotency and reducing lineage priming in G1. Furthermore, developmental competence was diminished, correlating with impaired exit from pluripotency. Collectively, this argues that epigenetic inheritance of histone modifications maintains a correctly balanced and dynamic chromatin landscape able to support mammalian cell differentiation.
    DOI:  https://doi.org/10.1038/s41588-023-01476-x
  8. Nat Biotechnol. 2023 Sep 07.
    MaxFuse enables data integration across weakly linked spatial and single-cell modalities.
      
    DOI:  https://doi.org/10.1038/s41587-023-01943-0
  9. Nat Immunol. 2023 Sep 07.
    CD8+ T cells pump the brakes on Alzheimer's disease.
    Katie L Reagin, Kristen E Funk.
      
    DOI:  https://doi.org/10.1038/s41590-023-01622-x
  10. Nat Commun. 2023 Sep 02. 14(1): 5362
    TAZ2 truncation confers overactivation of p300 and cellular vulnerability to HDAC inhibition.
    Longxia Xu, Hongwen Xuan, Wei He, Liang Zhang, Mengying Huang, Kuai Li, Hong Wen, Han Xu, Xiaobing Shi.
      The histone acetyltransferase p300/CBP is composed of several conserved domains, among which, the TAZ2 domain is known as a protein-protein interaction domain that binds to E1A and various transcription factors. Here we show that TAZ2 has a HAT autoinhibitory function. Truncating p300/CBP at TAZ2 leads to hyperactive HAT and elevated histone H3K27 and H3K18 acetylation in cells. Mechanistically, TAZ2 cooperates with other HAT neighboring domains to maintain the HAT active site in a 'closed' state. Truncating TAZ2 or binding of transcription factors to TAZ2 induces a conformational change that 'opens' the active site for substrate acetylation. Importantly, genetic mutations that lead to p300/CBP TAZ2 truncations are found in human cancers, and cells with TAZ2 truncations are vulnerable to histone deacetylase inhibitors. Our study reveals a function of the TAZ2 domain in HAT autoinhibitory regulation and provides a potential therapeutic strategy for the treatment of cancers harboring p300/CBP TAZ2 truncations.
    DOI:  https://doi.org/10.1038/s41467-023-41245-2
  11. Nat Commun. 2023 Sep 05. 14(1): 5405
    MKP1 promotes nonalcoholic steatohepatitis by suppressing AMPK activity through LKB1 nuclear retention.
    Bin Qiu, Ahmed Lawan, Chrysovalantou E Xirouchaki, Jae-Sung Yi, Marie Robert, Lei Zhang, Wendy Brown, Carlos Fernández-Hernando, Xiaoyong Yang, Tony Tiganis, Anton M Bennett.
      Nonalcoholic steatohepatitis (NASH) is triggered by hepatocyte death through activation of caspase 6, as a result of decreased adenosine monophosphate (AMP)-activated protein kinase-alpha (AMPKα) activity. Increased hepatocellular death promotes inflammation which drives hepatic fibrosis. We show that the nuclear-localized mitogen-activated protein kinase (MAPK) phosphatase-1 (MKP1) is upregulated in NASH patients and in NASH diet fed male mice. The focus of this work is to investigate whether and how MKP1 is involved in the development of NASH. Under NASH conditions increased oxidative stress, induces MKP1 expression leading to nuclear p38 MAPK dephosphorylation and decreases liver kinase B1 (LKB1) phosphorylation at a site required to promote LKB1 nuclear exit. Hepatic deletion of MKP1 in NASH diet fed male mice releases nuclear LKB1 into the cytoplasm to activate AMPKα and prevents hepatocellular death, inflammation and NASH. Hence, nuclear-localized MKP1-p38 MAPK-LKB1 signaling is required to suppress AMPKα which triggers hepatocyte death and the development of NASH.
    DOI:  https://doi.org/10.1038/s41467-023-41145-5
  12. Science. 2023 Sep 08. 381(6662): 1092-1098
    A type 2 immune circuit in the stomach controls mammalian adaptation to dietary chitin.
    Do-Hyun Kim, Yilin Wang, Haerin Jung, Rachael L Field, Xinya Zhang, Ta-Chiang Liu, Changqing Ma, James S Fraser, Jonathan R Brestoff, Steven J Van Dyken.
      Dietary fiber improves metabolic health, but host-encoded mechanisms for digesting fibrous polysaccharides are unclear. In this work, we describe a mammalian adaptation to dietary chitin that is coordinated by gastric innate immune activation and acidic mammalian chitinase (AMCase). Chitin consumption causes gastric distension and cytokine production by stomach tuft cells and group 2 innate lymphoid cells (ILC2s) in mice, which drives the expansion of AMCase-expressing zymogenic chief cells that facilitate chitin digestion. Although chitin influences gut microbial composition, ILC2-mediated tissue adaptation and gastrointestinal responses are preserved in germ-free mice. In the absence of AMCase, sustained chitin intake leads to heightened basal type 2 immunity, reduced adiposity, and resistance to obesity. These data define an endogenous metabolic circuit that enables nutrient extraction from an insoluble dietary constituent by enhancing digestive function.
    DOI:  https://doi.org/10.1126/science.add5649
  13. Nat Commun. 2023 Sep 08. 14(1): 5520
    Structures of liganded glycosylphosphatidylinositol transamidase illuminate GPI-AP biogenesis.
    Yidan Xu, Tingting Li, Zixuan Zhou, Jingjing Hong, Yulin Chao, Zhini Zhu, Ying Zhang, Qianhui Qu, Dianfan Li.
      Many eukaryotic receptors and enzymes rely on glycosylphosphatidylinositol (GPI) anchors for membrane localization and function. The transmembrane complex GPI-T recognizes diverse proproteins at a signal peptide region that lacks consensus sequence and replaces it with GPI via a transamidation reaction. How GPI-T maintains broad specificity while preventing unintentional cleavage is unclear. Here, substrates- and products-bound human GPI-T structures identify subsite features that enable broad proprotein specificity, inform catalytic mechanism, and reveal a multilevel safeguard mechanism against its promiscuity. In the absence of proproteins, the catalytic site is invaded by a locally stabilized loop. Activation requires energetically unfavorable rearrangements that transform the autoinhibitory loop into crucial catalytic cleft elements. Enzyme-proprotein binding in the transmembrane and luminal domains respectively powers the conformational rearrangement and induces a competent cleft. GPI-T thus integrates various weak specificity regions to form strong selectivity and prevent accidental activation. These findings provide important mechanistic insights into GPI-anchored protein biogenesis.
    DOI:  https://doi.org/10.1038/s41467-023-41281-y
  14. Nat Genet. 2023 Sep;55(9): 1448-1461
    GWAS of random glucose in 476,326 individuals provide insights into diabetes pathophysiology, complications and treatment stratification.
    GWA-PA Consortium
      Conventional measurements of fasting and postprandial blood glucose levels investigated in genome-wide association studies (GWAS) cannot capture the effects of DNA variability on 'around the clock' glucoregulatory processes. Here we show that GWAS meta-analysis of glucose measurements under nonstandardized conditions (random glucose (RG)) in 476,326 individuals of diverse ancestries and without diabetes enables locus discovery and innovative pathophysiological observations. We discovered 120 RG loci represented by 150 distinct signals, including 13 with sex-dimorphic effects, two cross-ancestry and seven rare frequency signals. Of these, 44 loci are new for glycemic traits. Regulatory, glycosylation and metagenomic annotations highlight ileum and colon tissues, indicating an underappreciated role of the gastrointestinal tract in controlling blood glucose. Functional follow-up and molecular dynamics simulations of lower frequency coding variants in glucagon-like peptide-1 receptor (GLP1R), a type 2 diabetes treatment target, reveal that optimal selection of GLP-1R agonist therapy will benefit from tailored genetic stratification. We also provide evidence from Mendelian randomization that lung function is modulated by blood glucose and that pulmonary dysfunction is a diabetes complication. Our investigation yields new insights into the biology of glucose regulation, diabetes complications and pathways for treatment stratification.
    DOI:  https://doi.org/10.1038/s41588-023-01462-3
  15. Nat Commun. 2023 Sep 07. 14(1): 5503
    Multifaceted membrane interactions of human Atg3 promote LC3-phosphatidylethanolamine conjugation during autophagy.
    Yansheng Ye, Erin R Tyndall, Van Bui, Maria C Bewley, Guifang Wang, Xupeng Hong, Yang Shen, John M Flanagan, Hong-Gang Wang, Fang Tian.
      Autophagosome formation, a crucial step in macroautophagy (autophagy), requires the covalent conjugation of LC3 proteins to the amino headgroup of phosphatidylethanolamine (PE) lipids. Atg3, an E2-like enzyme, catalyzes the transfer of LC3 from LC3-Atg3 to PEs in targeted membranes. Here we show that the catalytically important C-terminal regions of human Atg3 (hAtg3) are conformationally dynamic and directly interact with the membrane, in collaboration with its N-terminal membrane curvature-sensitive helix. The functional relevance of these interactions was confirmed by in vitro conjugation and in vivo cellular assays. Therefore, highly curved phagophoric rims not only serve as a geometric cue for hAtg3 recruitment, but also their interaction with hAtg3 promotes LC3-PE conjugation by targeting its catalytic center to the membrane surface and bringing substrates into proximity. Our studies advance the notion that autophagosome biogenesis is directly guided by the spatial interactions of Atg3 with highly curved phagophoric rims.
    DOI:  https://doi.org/10.1038/s41467-023-41243-4
  16. Nat Commun. 2023 Sep 06. 14(1): 5472
    NAD(H) homeostasis underlies host protection mediated by glycolytic myeloid cells in tuberculosis.
    Hayden T Pacl, Krishna C Chinta, Vineel P Reddy, Sajid Nadeem, Ritesh R Sevalkar, Kievershen Nargan, Kapongo Lumamba, Threnesan Naidoo, Joel N Glasgow, Anupam Agarwal, Adrie J C Steyn.
      Mycobacterium tuberculosis (Mtb) disrupts glycolytic flux in infected myeloid cells through an unclear mechanism. Flux through the glycolytic pathway in myeloid cells is inextricably linked to the availability of NAD+, which is maintained by NAD+ salvage and lactate metabolism. Using lung tissue from tuberculosis (TB) patients and myeloid deficient LDHA (LdhaLysM-/-) mice, we demonstrate that glycolysis in myeloid cells is essential for protective immunity in TB. Glycolytic myeloid cells are essential for the early recruitment of multiple classes of immune cells and IFNγ-mediated protection. We identify NAD+ depletion as central to the glycolytic inhibition caused by Mtb. Lastly, we show that the NAD+ precursor nicotinamide exerts a host-dependent, antimycobacterial effect, and that nicotinamide prophylaxis and treatment reduce Mtb lung burden in mice. These findings provide insight into how Mtb alters host metabolism through perturbation of NAD(H) homeostasis and reprogramming of glycolysis, highlighting this pathway as a potential therapeutic target.
    DOI:  https://doi.org/10.1038/s41467-023-40545-x
  17. Nature. 2023 Sep 06.
    Thymic mimetic cells function beyond self-tolerance.
    Tal Givony, Dena Leshkowitz, Diana Del Castillo, Shir Nevo, Noam Kadouri, Bareket Dassa, Yael Gruper, Razi Khalaila, Osher Ben-Nun, Tom Gome, Jan Dobeš, Shifra Ben-Dor, Merav Kedmi, Hadas Keren-Shaul, Rebecca Heffner-Krausz, Ziv Porat, Ofra Golani, Yoseph Addadi, Ori Brenner, David D Lo, Yael Goldfarb, Jakub Abramson.
      Development of immunocompetent T cells in the thymus is required for effective defence against all types of pathogens, including viruses, bacteria and fungi. To this end, T cells undergo a very strict educational program in the thymus, during which both non-functional and self-reactive T cell clones are eliminated by means of positive and negative selection1.Thymic epithelial cells (TECs) have an indispensable role in these processes, and previous studies have shown the notable heterogeneity of these cells2-7. Here, using multiomic analysis, we provide further insights into the functional and developmental diversity of TECs in mice, and reveal a detailed atlas of the TEC compartment according to cell transcriptional states and chromatin landscapes. Our analysis highlights unconventional TEC subsets that are similar to functionally well-defined parenchymal populations, including endocrine cells, microfold cells and myocytes. By focusing on the endocrine and microfold TEC populations, we show that endocrine TECs require Insm1 for their development and are crucial to maintaining thymus cellularity in a ghrelin-dependent manner; by contrast, microfold TECs require Spib for their development and are essential for the generation of thymic IgA+ plasma cells. Collectively, our study reveals that medullary TECs have the potential to differentiate into various types of molecularly distinct and functionally defined cells, which not only contribute to the induction of central tolerance, but also regulate the homeostasis of other thymus-resident populations.
    DOI:  https://doi.org/10.1038/s41586-023-06512-8
  18. Mol Cell. 2023 Aug 30. pii: S1097-2765(23)00643-3. [Epub ahead of print]
    eIF3d controls the persistent integrated stress response.
    Shaoni Mukhopadhyay, Maria E Amodeo, Amy S Y Lee.
      Cells respond to intrinsic and extrinsic stresses by reducing global protein synthesis and activating gene programs necessary for survival. Here, we show that the integrated stress response (ISR) is driven by the non-canonical cap-binding protein eIF3d that acts as a critical effector to control core stress response orchestrators, the translation factor eIF2α and the transcription factor ATF4. We find that during persistent stress, eIF3d activates the translation of the kinase GCN2, inducing eIF2α phosphorylation and inhibiting general protein synthesis. In parallel, eIF3d upregulates the m6A demethylase ALKBH5 to drive 5' UTR-specific demethylation of stress response genes, including ATF4. Ultimately, this cascade converges on ATF4 expression by increasing mRNA engagement of translation machinery and enhancing ribosome bypass of upstream open reading frames (uORFs). Our results reveal that eIF3d acts in a life-or-death decision point during chronic stress and uncover a synergistic signaling mechanism in which translational cascades complement transcriptional amplification to control essential cellular processes.
    Keywords:  ATF4; GCN2; RNA methylation; eIF3d; integrated stress response; m(6)A; translation regulation
    DOI:  https://doi.org/10.1016/j.molcel.2023.08.008
  19. Commun Biol. 2023 09 06. 6(1): 915
    Time-dependent cell-state selection identifies transiently expressed genes regulating ILC2 activation.
    Yumiko Tanaka, Mai Yamagishi, Yasutaka Motomura, Takashi Kamatani, Yusuke Oguchi, Nobutake Suzuki, Tsuyoshi Kiniwa, Hiroki Kabata, Misato Irie, Tatsuhiko Tsunoda, Fuyuki Miya, Keisuke Goda, Osamu Ohara, Takashi Funatsu, Koichi Fukunaga, Kazuyo Moro, Sotaro Uemura, Yoshitaka Shirasaki.
      The decision of whether cells are activated or not is controlled through dynamic intracellular molecular networks. However, the low population of cells during the transition state of activation renders the analysis of the transcriptome of this state technically challenging. To address this issue, we have developed the Time-Dependent Cell-State Selection (TDCSS) technique, which employs live-cell imaging of secretion activity to detect an index of the transition state, followed by the simultaneous recovery of indexed cells for subsequent transcriptome analysis. In this study, we used the TDCSS technique to investigate the transition state of group 2 innate lymphoid cells (ILC2s) activation, which is indexed by the onset of interleukin (IL)-13 secretion. The TDCSS approach allowed us to identify time-dependent genes, including transiently induced genes (TIGs). Our findings of IL4 and MIR155HG as TIGs have shown a regulatory function in ILC2s activation.
    DOI:  https://doi.org/10.1038/s42003-023-05297-w
  20. iScience. 2023 Oct 20. 26(10): 107719
    Metabolic and functional remodeling of colonic macrophages in response to high-fat diet-induced obesity.
    Angela Castoldi, David E Sanin, Nikki van Teijlingen Bakker, Cristhiane F Aguiar, Lauar de Brito Monteiro, Nisha Rana, Katarzyna M Grzes, Agnieszka M Kabat, Jonathan Curtis, Alanna M Cameron, George Caputa, Tiago Antônio de Souza, Fabrício O Souto, Joerg M Buescher, Joy Edwards-Hicks, Erika L Pearce, Edward J Pearce, Niels Olsen Saraiva Camara.
      Little is known about the effects of high-fat diet (HFD)-induced obesity on resident colonic lamina propria (LP) macrophages (LPMs) function and metabolism. Here, we report that obesity and diabetes resulted in increased macrophage infiltration in the colon. These macrophages exhibited the residency phenotype CX3CR1hiMHCIIhi and were CD4-TIM4-. During HFD, resident colonic LPM exhibited a lipid metabolism gene expression signature that overlapped that used to define lipid-associated macrophages (LAMs). Via single-cell RNA sequencing, we identified a sub-cluster of macrophages, increased in HFD, that were responsible for the LAM signature. Compared to other macrophages in the colon, these cells were characterized by elevated glycolysis, phagocytosis, and efferocytosis signatures. CX3CR1hiMHCIIhi colonic resident LPMs had fewer lipid droplets (LDs) and decreased triacylglycerol (TG) content compared to equivalent cells in lean mice and exhibited increased phagocytic capacity, suggesting that HFD induces adaptive responses in LPMs to limit bacterial translocation.
    Keywords:  Endocrinology; Immune response; Metabolomics
    DOI:  https://doi.org/10.1016/j.isci.2023.107719
  21. Dev Cell. 2023 Sep 01. pii: S1534-5807(23)00411-2. [Epub ahead of print]
    Mitochondrial leak metabolism induces the Spemann-Mangold Organizer via Hif-1α in Xenopus.
    Alexandra MacColl Garfinkel, Nelli Mnatsakanyan, Jeet H Patel, Andrea E Wills, Amy Shteyman, Peter J S Smith, Kambiz N Alavian, Elizabeth Ann Jonas, Mustafa K Khokha.
      An instructive role for metabolism in embryonic patterning is emerging, although a role for mitochondria is poorly defined. We demonstrate that mitochondrial oxidative metabolism establishes the embryonic patterning center, the Spemann-Mangold Organizer, via hypoxia-inducible factor 1α (Hif-1α) in Xenopus. Hypoxia or decoupling ATP production from oxygen consumption expands the Organizer by activating Hif-1α. In addition, oxygen consumption is 20% higher in the Organizer than in the ventral mesoderm, indicating an elevation in mitochondrial respiration. To reconcile increased mitochondrial respiration with activation of Hif-1α, we discovered that the "free" c-subunit ring of the F1Fo ATP synthase creates an inner mitochondrial membrane leak, which decouples ATP production from respiration at the Organizer, driving Hif-1α activation there. Overexpression of either the c-subunit or Hif-1α is sufficient to induce Organizer cell fates even when β-catenin is inhibited. We propose that mitochondrial leak metabolism could be a general mechanism for activating Hif-1α and Wnt signaling.
    Keywords:  F(1)F(o) ATP synthase; Hif-1α; LRPPRC; Spemann-Mangold Organizer; Wnt/β-catenin signaling; Xenopus; free c-subunit; hypoxia; metabolism; mitochondria
    DOI:  https://doi.org/10.1016/j.devcel.2023.08.015
  22. Nat Genet. 2023 Sep;55(9): 1555-1566
    Symmetric inheritance of parental histones contributes to safeguarding the fate of mouse embryonic stem cells during differentiation.
    Qing Wen, Jiaqi Zhou, Congcong Tian, Xinran Li, Guibing Song, Yuan Gao, Yaping Sun, Chiyuan Ma, Sitong Yao, Xiaoyan Liang, Xing Kang, Nan Wang, Yuan Yao, Hongbao Wang, Xiaohuan Liang, Jialin Tang, Steven M Offer, Xiaohua Lei, Chuanhe Yu, Xiangyu Liu, Zichuan Liu, Zhiquan Wang, Haiyun Gan.
      Parental histones, the carriers of posttranslational modifications, are deposited evenly onto the replicating DNA of sister chromatids in a process dependent on the Mcm2 subunit of DNA helicase and the Pole3 subunit of leading-strand DNA polymerase. The biological significance of parental histone propagation remains unclear. Here we show that Mcm2-mutated or Pole3-deleted mouse embryonic stem cells (ESCs) display aberrant histone landscapes and impaired neural differentiation. Mutation of the Mcm2 histone-binding domain causes defects in pre-implantation development and embryonic lethality. ESCs with biased parental histone transfer exhibit increased epigenetic heterogeneity, showing altered histone variant H3.3 and H3K27me3 patterning at genomic sites regulating differentiation genes. Our results indicate that the lagging strand pattern of H3.3 leads to the redistribution of H3K27me3 in Mcm2-2A ESCs. We demonstrate that symmetric parental histone deposition to sister chromatids contributes to cellular differentiation and development.
    DOI:  https://doi.org/10.1038/s41588-023-01477-w
  23. Nat Commun. 2023 Sep 06. 14(1): 5195
    A super-enhancer-regulated RNA-binding protein cascade drives pancreatic cancer.
    Corina E Antal, Tae Gyu Oh, Stefan Aigner, En-Ching Luo, Brian A Yee, Tania Campos, Hervé Tiriac, Katherine L Rothamel, Zhang Cheng, Henry Jiao, Allen Wang, Nasun Hah, Elizabeth Lenkiewicz, Jan C Lumibao, Morgan L Truitt, Gabriela Estepa, Ester Banayo, Senada Bashi, Edgar Esparza, Ruben M Munoz, Jolene K Diedrich, Nicole M Sodir, Jasmine R Mueller, Cory R Fraser, Erkut Borazanci, David Propper, Daniel D Von Hoff, Christopher Liddle, Ruth T Yu, Annette R Atkins, Haiyong Han, Andrew M Lowy, Michael T Barrett, Dannielle D Engle, Gerard I Evan, Gene W Yeo, Michael Downes, Ronald M Evans.
      Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy in need of new therapeutic options. Using unbiased analyses of super-enhancers (SEs) as sentinels of core genes involved in cell-specific function, here we uncover a druggable SE-mediated RNA-binding protein (RBP) cascade that supports PDAC growth through enhanced mRNA translation. This cascade is driven by a SE associated with the RBP heterogeneous nuclear ribonucleoprotein F, which stabilizes protein arginine methyltransferase 1 (PRMT1) to, in turn, control the translational mediator ubiquitin-associated protein 2-like. All three of these genes and the regulatory SE are essential for PDAC growth and coordinately regulated by the Myc oncogene. In line with this, modulation of the RBP network by PRMT1 inhibition reveals a unique vulnerability in Myc-high PDAC patient organoids and markedly reduces tumor growth in male mice. Our study highlights a functional link between epigenetic regulation and mRNA translation and identifies components that comprise unexpected therapeutic targets for PDAC.
    DOI:  https://doi.org/10.1038/s41467-023-40798-6
  24. Nat Commun. 2023 Sep 05. 14(1): 5418
    Neutrophil metalloproteinase driven spleen damage hampers infection control of trypanosomiasis.
    Hien Thi Thu Pham, Stefan Magez, Boyoon Choi, Bolortsetseg Baatar, Joohee Jung, Magdalena Radwanska.
      Recent blood transcriptomic analysis of rhodesiense sleeping sickness patients has revealed that neutrophil signature genes and activation markers constitute the top indicators of trypanosomiasis-associated inflammation. Here, we show that Trypanosoma brucei infection results in expansion and differentiation of four splenic neutrophil subpopulations, including Mki67+Birc5+Gfi1+Cebpe+ proliferation-competent precursors, two intermediate immature subpopulations and Cebpb+Spi1+Irf7+Mcl1+Csf3r+ inflammation reprogrammed mature neutrophils. Transcriptomic scRNA-seq profiling identified the largest immature subpopulation by Mmp8/9 positive tertiary granule markers. We confirmed the presence of both metalloproteinases in extracellular spleen homogenates and plasma. During infection, these enzymes digest extracellular matrix components in the absence of sufficient TIMP inhibitory activity, driving remodeling of the spleen follicular architecture. Neutrophil depletion prevents the occurrence of organ damage, resulting in increased plasma cell numbers and prolonged host survival. We conclude that trypanosomiasis-associated neutrophil activation is a major contributor to the destruction of the secondary lymphoid architecture, required for maintaining an efficient adaptive immune response.
    DOI:  https://doi.org/10.1038/s41467-023-41089-w
  25. Nat Rev Immunol. 2023 Sep 04.
    Orally delivered lactate-producing bacteria limit CNS autoimmunity.
    Kirsty Minton.
      
    DOI:  https://doi.org/10.1038/s41577-023-00938-x
  26. Nat Commun. 2023 Sep 08. 14(1): 5536
    Shared and distinct genetic etiologies for different types of clonal hematopoiesis.
    Derek W Brown, Liam D Cato, Yajie Zhao, Satish K Nandakumar, Erik L Bao, Eugene J Gardner, Aubrey K Hubbard, Alexander DePaulis, Thomas Rehling, Lei Song, Kai Yu, Stephen J Chanock, John R B Perry, Vijay G Sankaran, Mitchell J Machiela.
      Clonal hematopoiesis (CH)-age-related expansion of mutated hematopoietic clones-can differ in frequency and cellular fitness by CH type (e.g., mutations in driver genes (CHIP), gains/losses and copy-neutral loss of chromosomal segments (mCAs), and loss of sex chromosomes). Co-occurring CH raises questions as to their origin, selection, and impact. We integrate sequence and genotype array data in up to 482,378 UK Biobank participants to demonstrate shared genetic architecture across CH types. Our analysis suggests a cellular evolutionary trade-off between different types of CH, with LOY occurring at lower rates in individuals carrying mutations in established CHIP genes. We observed co-occurrence of CHIP and mCAs with overlap at TET2, DNMT3A, and JAK2, in which CHIP precedes mCA acquisition. Furthermore, individuals carrying overlapping CH had high risk of future lymphoid and myeloid malignancies. Finally, we leverage shared genetic architecture of CH traits to identify 15 novel loci associated with leukemia risk.
    DOI:  https://doi.org/10.1038/s41467-023-41315-5
  27. Nat Genet. 2023 Sep;55(9): 1421
    The complex relationship between cell transcriptomic state and phenotype.
    Michael Fletcher.
      
    DOI:  https://doi.org/10.1038/s41588-023-01511-x
  28. Mol Cell. 2023 Sep 07. pii: S1097-2765(23)00641-X. [Epub ahead of print]83(17): 3188-3204.e7
    Damaged mitochondria recruit the effector NEMO to activate NF-κB signaling.
    Olivia Harding, Elisabeth Holzer, Julia F Riley, Sascha Martens, Erika L F Holzbaur.
      Failure to clear damaged mitochondria via mitophagy disrupts physiological function and may initiate damage signaling via inflammatory cascades, although how these pathways intersect remains unclear. We discovered that nuclear factor kappa B (NF-κB) essential regulator NF-κB effector molecule (NEMO) is recruited to damaged mitochondria in a Parkin-dependent manner in a time course similar to recruitment of the structurally related mitophagy adaptor, optineurin (OPTN). Upon recruitment, NEMO partitions into phase-separated condensates distinct from OPTN but colocalizing with p62/SQSTM1. NEMO recruitment, in turn, recruits the active catalytic inhibitor of kappa B kinase (IKK) component phospho-IKKβ, initiating NF-κB signaling and the upregulation of inflammatory cytokines. Consistent with a potential neuroinflammatory role, NEMO is recruited to mitochondria in primary astrocytes upon oxidative stress. These findings suggest that damaged, ubiquitinated mitochondria serve as an intracellular platform to initiate innate immune signaling, promoting the formation of activated IKK complexes sufficient to activate NF-κB signaling. We propose that mitophagy and NF-κB signaling are initiated as parallel pathways in response to mitochondrial stress.
    Keywords:  ALS; NEMO; NF-κB; NF-κB effector molecule; Parkin; Parkinson’s disease; SQSTM1/p62; amyotrophic lateral sclerosis; cell stress; innate immunity; mitophagy; neurodegeneration; neuroinflammation; optineurin nuclear factor kappa B; phase separation; ubiquitin
    DOI:  https://doi.org/10.1016/j.molcel.2023.08.005
  29. Nat Commun. 2023 Sep 02. 14(1): 5336
    Epigenetic inheritance is unfaithful at intermediately methylated CpG sites.
    Amir D Hay, Noah J Kessler, Daniel Gebert, Nozomi Takahashi, Hugo Tavares, Felipe K Teixeira, Anne C Ferguson-Smith.
      DNA methylation at the CpG dinucleotide is considered a stable epigenetic mark due to its presumed long-term inheritance through clonal expansion. Here, we perform high-throughput bisulfite sequencing on clonally derived somatic cell lines to quantitatively measure methylation inheritance at the nucleotide level. We find that although DNA methylation is generally faithfully maintained at hypo- and hypermethylated sites, this is not the case at intermediately methylated CpGs. Low fidelity intermediate methylation is interspersed throughout the genome and within genes with no or low transcriptional activity, and is not coordinately maintained between neighbouring sites. We determine that the probabilistic changes that occur at intermediately methylated sites are likely due to DNMT1 rather than DNMT3A/3B activity. The observed lack of clonal inheritance at intermediately methylated sites challenges the current epigenetic inheritance model and has direct implications for both the functional relevance and general interpretability of DNA methylation as a stable epigenetic mark.
    DOI:  https://doi.org/10.1038/s41467-023-40845-2
  30. Nat Commun. 2023 Sep 06. 14(1): 5456
    A cytotoxic T cell inspired oncolytic nanosystem promotes lytic cell death by lipid peroxidation and elicits antitumor immune responses.
    Zhigui Zuo, Hao Yin, Yu Zhang, Congying Xie, Qinyang Wang.
      Lytic cell death triggers an antitumour immune response. However, cancer cells evade lytic cell death by several mechanisms. Moreover, a prolonged and uncontrolled immune response conversely leads to T-cell exhaustion. Therefore, an oncolytic system capable of eliciting an immune response by killing cancer cells in a controlled manner is needed. Here, we establish a micro-scale cytotoxic T-cell-inspired oncolytic system (TIOs) to precisely lyse cancer cells by NIR-light-controlled lipid peroxidation. Our TIOs present antigen-based cell recognition, tumour-targeting and catalytic cell-lysis ability; thus, the TIOs induce oncolysis in vivo. We apply TIOs to preclinical cancer models, showing anti-tumor activity with negligible side-effects. Tumour regression is correlated with a T-cell based anti-tumour immune response and TIOs also improve responses to anti-PD-1 therapy or STING activation. Our study provides insights to design oncolytic systems for antitumour immunity. Moreover, activation of STING can reverse T-cell exhaustion in oncolysis.
    DOI:  https://doi.org/10.1038/s41467-023-41335-1
  31. Nat Commun. 2023 Sep 02. 14(1): 5341
    Ascl1 and Ngn2 convert mouse embryonic stem cells to neurons via functionally distinct paths.
    Gintautas Vainorius, Maria Novatchkova, Georg Michlits, Juliane Christina Baar, Cecilia Raupach, Joonsun Lee, Ramesh Yelagandula, Marius Wernig, Ulrich Elling.
      Ascl1 and Ngn2, closely related proneural transcription factors, are able to convert mouse embryonic stem cells into induced neurons. Despite their similarities, these factors elicit only partially overlapping transcriptional programs, and it remains unknown whether cells are converted via distinct mechanisms. Here we show that Ascl1 and Ngn2 induce mutually exclusive side populations by binding and activating distinct lineage drivers. Furthermore, Ascl1 rapidly dismantles the pluripotency network and installs neuronal and trophoblast cell fates, while Ngn2 generates a neural stem cell-like intermediate supported by incomplete shutdown of the pluripotency network. Using CRISPR-Cas9 knockout screening, we find that Ascl1 relies more on factors regulating pluripotency and the cell cycle, such as Tcf7l1. In the absence of Tcf7l1, Ascl1 still represses core pluripotency genes but fails to exit the cell cycle. However, overexpression of Cdkn1c induces cell cycle exit and restores the generation of neurons. These findings highlight that cell type conversion can occur through two distinct mechanistic paths, even when induced by closely related transcription factors.
    DOI:  https://doi.org/10.1038/s41467-023-40803-y
  32. Nat Commun. 2023 Sep 08. 14(1): 5524
    CD44 connects autophagy decline and ageing in the vascular endothelium.
    Lu Zhang, Peichang Yang, Jingxuan Chen, Zhiqiang Chen, Zhihui Liu, Gaoqing Feng, Fangfang Sha, Zirui Li, Zaoyi Xu, Yating Huang, Xiaotong Shi, Xuebiao Li, Jiatian Cui, Chenyi Zhang, Pei Fan, Liuqing Cui, Yunpeng Shen, Guangzhou Zhou, Hongjuan Jing, Shiwei Ma.
      The decline of endothelial autophagy is closely related to vascular senescence and disease, although the molecular mechanisms connecting these outcomes in vascular endothelial cells (VECs) remain unclear. Here, we identify a crucial role for CD44, a multifunctional adhesion molecule, in controlling autophagy and ageing in VECs. The CD44 intercellular domain (CD44ICD) negatively regulates autophagy by reducing PIK3R4 and PIK3C3 levels and disrupting STAT3-dependent PtdIns3K complexes. CD44 and its homologue clec-31 are increased in ageing vascular endothelium and Caenorhabditis elegans, respectively, suggesting that an age-dependent increase in CD44 induces autophagy decline and ageing phenotypes. Accordingly, CD44 knockdown ameliorates age-associated phenotypes in VECs. The endothelium-specific CD44ICD knock-in mouse is shorter-lived, with VECs exhibiting obvious premature ageing characteristics associated with decreased basal autophagy. Autophagy activation suppresses the premature ageing of human and mouse VECs overexpressing CD44ICD, function conserved in the CD44 homologue clec-31 in C. elegans. Our work describes a mechanism coordinated by CD44 function bridging autophagy decline and ageing.
    DOI:  https://doi.org/10.1038/s41467-023-41346-y
  33. Nat Commun. 2023 Sep 05. 14(1): 5411
    A tissue-intrinsic IL-33/EGF circuit promotes epithelial regeneration after intestinal injury.
    Marco Calafiore, Ya-Yuan Fu, Paola Vinci, Viktor Arnhold, Winston Y Chang, Suze A Jansen, Anastasiya Egorova, Shuichiro Takashima, Jason Kuttiyara, Takahiro Ito, Jonathan Serody, Susumu Nakae, Heth Turnquist, Johan van Es, Hans Clevers, Caroline A Lindemans, Bruce R Blazar, Alan M Hanash.
      Intestinal stem cells (ISCs) maintain the epithelial lining of the intestines, but mechanisms regulating ISCs and their niche after damage remain poorly understood. Utilizing radiation injury to model intestinal pathology, we report here that the Interleukin-33 (IL-33)/ST2 axis, an immunomodulatory pathway monitored clinically as an intestinal injury biomarker, regulates intrinsic epithelial regeneration by inducing production of epidermal growth factor (EGF). Three-dimensional imaging and lineage-specific RiboTag induction within the stem cell compartment indicated that ISCs expressed IL-33 in response to radiation injury. Neighboring Paneth cells responded to IL-33 by augmenting production of EGF, which promoted ISC recovery and epithelial regeneration. These findings reveal an unknown pathway of niche regulation and crypt regeneration whereby the niche responds dynamically upon injury and the stem cells orchestrate regeneration by regulating their niche. This regenerative circuit also highlights the breadth of IL-33 activity beyond immunomodulation and the therapeutic potential of EGF administration for treatment of intestinal injury.
    DOI:  https://doi.org/10.1038/s41467-023-40993-5
  34. Nat Commun. 2023 Sep 06. 14(1): 5451
    Hyodeoxycholic acid ameliorates nonalcoholic fatty liver disease by inhibiting RAN-mediated PPARα nucleus-cytoplasm shuttling.
    Jing Zhong, Xiaofang He, Xinxin Gao, Qiaohong Liu, Yu Zhao, Ying Hong, Weize Zhu, Juan Yan, Yifan Li, Yan Li, Ningning Zheng, Yiyang Bao, Hao Wang, Junli Ma, Wenjin Huang, Zekun Liu, Yuanzhi Lyu, Xisong Ke, Wei Jia, Cen Xie, Yiyang Hu, Lili Sheng, Houkai Li.
      Nonalcoholic fatty liver disease (NAFLD) is usually characterized with disrupted bile acid (BA) homeostasis. However, the exact role of certain BA in NAFLD is poorly understood. Here we show levels of serum hyodeoxycholic acid (HDCA) decrease in both NAFLD patients and mice, as well as in liver and intestinal contents of NAFLD mice compared to their healthy counterparts. Serum HDCA is also inversely correlated with NAFLD severity. Dietary HDCA supplementation ameliorates diet-induced NAFLD in male wild type mice by activating fatty acid oxidation in hepatic peroxisome proliferator-activated receptor α (PPARα)-dependent way because the anti-NAFLD effect of HDCA is abolished in hepatocyte-specific Pparα knockout mice. Mechanistically, HDCA facilitates nuclear localization of PPARα by directly interacting with RAN protein. This interaction disrupts the formation of RAN/CRM1/PPARα nucleus-cytoplasm shuttling heterotrimer. Our results demonstrate the therapeutic potential of HDCA for NAFLD and provide new insights of BAs on regulating fatty acid metabolism.
    DOI:  https://doi.org/10.1038/s41467-023-41061-8
  35. EMBO Rep. 2023 Sep 06. e57600
    The obesity-linked human lncRNA AATBC stimulates mitochondrial function in adipocytes.
    Maude Giroud, Stefan Kotschi, Yun Kwon, Ophélia Le Thuc, Anne Hoffmann, Manuel Gil-Lozano, Michael Karbiener, Juan Carlos Higareda-Almaraz, Sajjad Khani, Daniel Tews, Pamela Fischer-Posovszky, Wenfei Sun, Hua Dong, Adhideb Ghosh, Christian Wolfrum, Martin Wabitsch, Kirsi A Virtanen, Matthias Blüher, Søren Nielsen, Anja Zeigerer, Cristina García-Cáceres, Marcel Scheideler, Stephan Herzig, Alexander Bartelt.
      Adipocytes are critical regulators of metabolism and energy balance. While white adipocyte dysfunction is a hallmark of obesity-associated disorders, thermogenic adipocytes are linked to cardiometabolic health. As adipocytes dynamically adapt to environmental cues by functionally switching between white and thermogenic phenotypes, a molecular understanding of this plasticity could help improving metabolism. Here, we show that the lncRNA Apoptosis associated transcript in bladder cancer (AATBC) is a human-specific regulator of adipocyte plasticity. Comparing transcriptional profiles of human adipose tissues and cultured adipocytes we discovered that AATBC was enriched in thermogenic conditions. Using primary and immortalized human adipocytes we found that AATBC enhanced the thermogenic phenotype, which was linked to increased respiration and a more fragmented mitochondrial network. Expression of AATBC in adipose tissue of mice led to lower plasma leptin levels. Interestingly, this association was also present in human subjects, as AATBC in adipose tissue was inversely correlated with plasma leptin levels, BMI, and other measures of metabolic health. In conclusion, AATBC is a novel obesity-linked regulator of adipocyte plasticity and mitochondrial function in humans.
    Keywords:  adipocyte; mitochondrial dynamics; non-coding RNA; obesity; thermogenesis
    DOI:  https://doi.org/10.15252/embr.202357600
  36. Nature. 2023 Sep 06.
    Polθ is phosphorylated by PLK1 to repair double-strand breaks in mitosis.
    Camille Gelot, Marton Tibor Kovacs, Simona Miron, Emilie Mylne, Alexis Haan, Liza Boeffard-Dosierre, Rania Ghouil, Tatiana Popova, Florent Dingli, Damarys Loew, Josée Guirouilh-Barbat, Elaine Del Nery, Sophie Zinn-Justin, Raphael Ceccaldi.
      DNA double-strand breaks (DSBs) are deleterious lesions that challenge genome integrity. To mitigate this threat, human cells rely on the activity of multiple DNA repair machineries that are tightly regulated throughout the cell cycle1. In interphase, DSBs are mainly repaired by non-homologous end joining and homologous recombination2. However, these pathways are completely inhibited in mitosis3-5, leaving the fate of mitotic DSBs unknown. Here we show that DNA polymerase theta6 (Polθ) repairs mitotic DSBs and thereby maintains genome integrity. In contrast to other DSB repair factors, Polθ function is activated in mitosis upon phosphorylation by Polo-like kinase 1 (PLK1). Phosphorylated Polθ is recruited by a direct interaction with the BRCA1 C-terminal domains of TOPBP1 to mitotic DSBs, where it mediates joining of broken DNA ends. Loss of Polθ leads to defective repair of mitotic DSBs, resulting in a loss of genome integrity. This is further exacerbated in cells that are deficient in homologous recombination, where loss of mitotic DSB repair by Polθ results in cell death. Our results identify mitotic DSB repair as the underlying cause of synthetic lethality between Polθ and homologous recombination. Together, our findings reveal the critical importance of mitotic DSB repair in the maintenance of genome integrity.
    DOI:  https://doi.org/10.1038/s41586-023-06506-6
  37. Immunity. 2023 Aug 29. pii: S1074-7613(23)00364-3. [Epub ahead of print]
    Genetic variants of phospholipase C-γ2 alter the phenotype and function of microglia and confer differential risk for Alzheimer's disease.
    Andy P Tsai, Chuanpeng Dong, Peter Bor-Chian Lin, Adrian L Oblak, Gonzalo Viana Di Prisco, Nian Wang, Nicole Hajicek, Adam J Carr, Emma K Lendy, Oliver Hahn, Micaiah Atkins, Aulden G Foltz, Jheel Patel, Guixiang Xu, Miguel Moutinho, John Sondek, Qisheng Zhang, Andrew D Mesecar, Yunlong Liu, Brady K Atwood, Tony Wyss-Coray, Kwangsik Nho, Stephanie J Bissel, Bruce T Lamb, Gary E Landreth.
      Genetic association studies have demonstrated the critical involvement of the microglial immune response in Alzheimer's disease (AD) pathogenesis. Phospholipase C-gamma-2 (PLCG2) is selectively expressed by microglia and functions in many immune receptor signaling pathways. In AD, PLCG2 is induced uniquely in plaque-associated microglia. A genetic variant of PLCG2, PLCG2P522R, is a mild hypermorph that attenuates AD risk. Here, we identified a loss-of-function PLCG2 variant, PLCG2M28L, that confers an increased AD risk. PLCG2P522R attenuated disease in an amyloidogenic murine AD model, whereas PLCG2M28L exacerbated the plaque burden associated with altered phagocytosis and Aβ clearance. The variants bidirectionally modulated disease pathology by inducing distinct transcriptional programs that identified microglial subpopulations associated with protective or detrimental phenotypes. These findings identify PLCG2M28L as a potential AD risk variant and demonstrate that PLCG2 variants can differentially orchestrate microglial responses in AD pathogenesis that can be therapeutically targeted.
    Keywords:  Alzheimer’s disease; P522R and M28L variant; amyloid pathology; microglia; microglia-plaque interactions; microglial uptake capacity; neuroinflammation; phospholipase C-gamma-2; synaptic function; transcriptional programs
    DOI:  https://doi.org/10.1016/j.immuni.2023.08.008
  38. Sci Adv. 2023 Sep 08. 9(36): eadf9904
    Infection-experienced HSPCs protect against infections by generating neutrophils with enhanced mitochondrial bactericidal activity.
    Hannah Darroch, Pramuk Keerthisinghe, Yih Jian Sung, Leah Rolland, Anneke Prankerd-Gough, Philip S Crosier, Jonathan W Astin, Christopher J Hall.
      Hematopoietic stem and progenitor cells (HSPCs) respond to infection by proliferating and generating in-demand neutrophils through a process called emergency granulopoiesis (EG). Recently, infection-induced changes in HSPCs have also been shown to underpin the longevity of trained immunity, where they generate innate immune cells with enhanced responses to subsequent microbial threats. Using larval zebrafish to live image neutrophils and HSPCs, we show that infection-experienced HSPCs generate neutrophils with enhanced bactericidal functions. Transcriptomic analysis of EG neutrophils uncovered a previously unknown function for mitochondrial reactive oxygen species in elevating neutrophil bactericidal activity. We also reveal that driving expression of zebrafish C/EBPβ within infection-naïve HSPCs is sufficient to generate neutrophils with similarly enhanced bactericidal capacity. Our work suggests that this demand-adapted source of neutrophils contributes to trained immunity by providing enhanced protection toward subsequent infections. Manipulating demand-driven granulopoiesis may provide a therapeutic strategy to boost neutrophil function and treat infectious disease.
    DOI:  https://doi.org/10.1126/sciadv.adf9904
  39. Nat Commun. 2023 Sep 06. 14(1): 5438
    Direct observation of tRNA-chaperoned folding of a dynamic mRNA ensemble.
    Krishna C Suddala, Janghyun Yoo, Lixin Fan, Xiaobing Zuo, Yun-Xing Wang, Hoi Sung Chung, Jinwei Zhang.
      T-box riboswitches are multi-domain noncoding RNAs that surveil individual amino acid availabilities in most Gram-positive bacteria. T-boxes directly bind specific tRNAs, query their aminoacylation status to detect starvation, and feedback control the transcription or translation of downstream amino-acid metabolic genes. Most T-boxes rapidly recruit their cognate tRNA ligands through an intricate three-way stem I-stem II-tRNA interaction, whose establishment is not understood. Using single-molecule FRET, SAXS, and time-resolved fluorescence, we find that the free T-box RNA assumes a broad distribution of open, semi-open, and closed conformations that only slowly interconvert. tRNA directly binds all three conformers with distinct kinetics, triggers nearly instantaneous collapses of the open conformations, and returns the T-box RNA to their pre-binding conformations upon dissociation. This scissors-like dynamic behavior is enabled by a hinge-like pseudoknot domain which poises the T-box for rapid tRNA-induced domain closure. This study reveals tRNA-chaperoned folding of flexible, multi-domain mRNAs through a Venus flytrap-like mechanism.
    DOI:  https://doi.org/10.1038/s41467-023-41155-3
  40. Nat Chem Biol. 2023 Sep 07.
    Design principles for cyclin K molecular glue degraders.
    Zuzanna Kozicka, Dakota J Suchyta, Vivian Focht, Georg Kempf, Georg Petzold, Marius Jentzsch, Charles Zou, Cristina Di Genua, Katherine A Donovan, Seemon Coomar, Marko Cigler, Cristina Mayor-Ruiz, Jonathan L Schmid-Burgk, Daniel Häussinger, Georg E Winter, Eric S Fischer, Mikołaj Słabicki, Dennis Gillingham, Benjamin L Ebert, Nicolas H Thomä.
      Molecular glue degraders are an effective therapeutic modality, but their design principles are not well understood. Recently, several unexpectedly diverse compounds were reported to deplete cyclin K by linking CDK12-cyclin K to the DDB1-CUL4-RBX1 E3 ligase. Here, to investigate how chemically dissimilar small molecules trigger cyclin K degradation, we evaluated 91 candidate degraders in structural, biophysical and cellular studies and reveal all compounds acquire glue activity via simultaneous CDK12 binding and engagement of DDB1 interfacial residues, in particular Arg928. While we identify multiple published kinase inhibitors as cryptic degraders, we also show that these glues do not require pronounced inhibitory properties for activity and that the relative degree of CDK12 inhibition versus cyclin K degradation is tuneable. We further demonstrate cyclin K degraders have transcriptional signatures distinct from CDK12 inhibitors, thereby offering unique therapeutic opportunities. The systematic structure-activity relationship analysis presented herein provides a conceptual framework for rational molecular glue design.
    DOI:  https://doi.org/10.1038/s41589-023-01409-z
  41. Nat Commun. 2023 Sep 07. 14(1): 5491
    Plant immunity suppression by an exo-β-1,3-glucanase and an elongation factor 1α of the rice blast fungus.
    Hang Liu, Xunli Lu, Mengfei Li, Zhiqin Lun, Xia Yan, Changfa Yin, Guixin Yuan, Xingbin Wang, Ning Liu, Di Liu, Mian Wu, Ziluolong Luo, Yan Zhang, Vijai Bhadauria, Jun Yang, Nicholas J Talbot, You-Liang Peng.
      Fungal cell walls undergo continual remodeling that generates β-1,3-glucan fragments as products of endo-glycosyl hydrolases (GHs), which can be recognized as pathogen-associated molecular patterns (PAMPs) and trigger plant immune responses. How fungal pathogens suppress those responses is often poorly understood. Here, we study mechanisms underlying the suppression of β-1,3-glucan-triggered plant immunity by the blast fungus Magnaporthe oryzae. We show that an exo-β-1,3-glucanase of the GH17 family, named Ebg1, is important for fungal cell wall integrity and virulence of M. oryzae. Ebg1 can hydrolyze β-1,3-glucan and laminarin into glucose, thus suppressing β-1,3-glucan-triggered plant immunity. However, in addition, Ebg1 seems to act as a PAMP, independent of its hydrolase activity. This Ebg1-induced immunity appears to be dampened by the secretion of an elongation factor 1 alpha protein (EF1α), which interacts and co-localizes with Ebg1 in the apoplast. Future work is needed to understand the mechanisms behind Ebg1-induced immunity and its suppression by EF1α.
    DOI:  https://doi.org/10.1038/s41467-023-41175-z
  42. Nat Commun. 2023 Sep 02. 14(1): 5354
    Deciphering early human pancreas development at the single-cell level.
    Zhuo Ma, Xiaofei Zhang, Wen Zhong, Hongyan Yi, Xiaowei Chen, Yinsuo Zhao, Yanlin Ma, Eli Song, Tao Xu.
      Understanding pancreas development can provide clues for better treatments of pancreatic diseases. However, the molecular heterogeneity and developmental trajectory of the early human pancreas are poorly explored. Here, we performed large-scale single-cell RNA sequencing and single-cell assay for transposase accessible chromatin sequencing of human embryonic pancreas tissue obtained from first-trimester embryos. We unraveled the molecular heterogeneity, developmental trajectories and regulatory networks of the major cell types. The results reveal that dorsal pancreatic multipotent cells in humans exhibit different gene expression patterns than ventral multipotent cells. Pancreato-biliary progenitors that generate ventral multipotent cells in humans were identified. Notch and MAPK signals from mesenchymal cells regulate the differentiation of multipotent cells into trunk and duct cells. Notably, we identified endocrine progenitor subclusters with different differentiation potentials. Although the developmental trajectories are largely conserved between humans and mice, some distinct gene expression patterns have also been identified. Overall, we provide a comprehensive landscape of early human pancreas development to understand its lineage transitions and molecular complexity.
    DOI:  https://doi.org/10.1038/s41467-023-40893-8
  43. Nat Struct Mol Biol. 2023 Sep 07.
    Regulation with cell size ensures mitochondrial DNA homeostasis during cell growth.
    Anika Seel, Francesco Padovani, Moritz Mayer, Alissa Finster, Daniela Bureik, Felix Thoma, Christof Osman, Till Klecker, Kurt M Schmoller.
      To maintain stable DNA concentrations, proliferating cells need to coordinate DNA replication with cell growth. For nuclear DNA, eukaryotic cells achieve this by coupling DNA replication to cell-cycle progression, ensuring that DNA is doubled exactly once per cell cycle. By contrast, mitochondrial DNA replication is typically not strictly coupled to the cell cycle, leaving the open question of how cells maintain the correct amount of mitochondrial DNA during cell growth. Here, we show that in budding yeast, mitochondrial DNA copy number increases with cell volume, both in asynchronously cycling populations and during G1 arrest. Our findings suggest that cell-volume-dependent mitochondrial DNA maintenance is achieved through nuclear-encoded limiting factors, including the mitochondrial DNA polymerase Mip1 and the packaging factor Abf2, whose amount increases in proportion to cell volume. By directly linking mitochondrial DNA maintenance to nuclear protein synthesis and thus cell growth, constant mitochondrial DNA concentrations can be robustly maintained without a need for cell-cycle-dependent regulation.
    DOI:  https://doi.org/10.1038/s41594-023-01091-8
  44. Nat Metab. 2023 Sep 07.
    Alleviating symptoms of neurodegenerative disorders by astrocyte-specific overexpression of TMEM164 in mice.
    Liansheng Zhang, Zhiheng Jia, Qiang Wu, Tao Bai, Bo Wang, Xinde Hu, Tianwen Li, Xingyu Liu, Jiqiang Fu, Yuelei Chen, Xiaoyan Ding, Zhen Liu, Zhengzheng Xu, Haibo Zhou.
      Neuroinflammatory microglia secrete cytokines to induce neurotoxic reactive astrocytes, which are one of the major causes of neuronal death. However, the intrinsic key regulators underlying neurotoxic reactive astrocytes induction are unknown. Here we show that the transmembrane protein 164 (TMEM164) is an early-response intrinsic factor that regulates neurotoxic astrocyte reactivity. TMEM164 overexpression inhibits the induction of neurotoxic reactive astrocytes, maintains normal astrocytic functions and suppresses neurotoxic reactive astrocyte-mediated neuronal death by decreasing the secretion of neurotoxic saturated lipids. Adeno-associated virus-mediated, astrocyte-specific TMEM164 overexpression in male and female mice prevents the induction of neurotoxic reactive astrocytes, dopaminergic neuronal loss and motor deficits in a Parkinson's disease model. Notably, brain-wide astrocyte-specific TMEM164 overexpression prevents the induction of neurotoxic reactive astrocytes, amyloid β deposition, neurodegeneration and memory decline in the 5XFAD Alzheimer's disease mouse model, suggesting that TMEM164 could serve as a potential therapeutic target for neurodegenerative disorders.
    DOI:  https://doi.org/10.1038/s42255-023-00887-8
  45. Nat Commun. 2023 Sep 08. 14(1): 5547
    Serotonin signaling regulates actomyosin contractility during morphogenesis in evolutionarily divergent lineages.
    Sanjay Karki, Mehdi Saadaoui, Valentin Dunsing, Stephen Kerridge, Elise Da Silva, Jean-Marc Philippe, Cédric Maurange, Thomas Lecuit.
      Serotonin is a neurotransmitter that signals through 5-HT receptors to control key functions in the nervous system. Serotonin receptors are also ubiquitously expressed in various organs and have been detected in embryos of different organisms. Potential morphogenetic functions of serotonin signaling have been proposed based on pharmacological studies but a mechanistic understanding is still lacking. Here, we uncover a role of serotonin signaling in axis extension of Drosophila embryos by regulating Myosin II (MyoII) activation, cell contractility and cell intercalation. We find that serotonin and serotonin receptors 5HT2A and 5HT2B form a signaling module that quantitatively regulates the amplitude of planar polarized MyoII contractility specified by Toll receptors and the GPCR Cirl. Remarkably, serotonin signaling also regulates actomyosin contractility at cell junctions, cellular flows and epiblast morphogenesis during chicken gastrulation. This phylogenetically conserved mechanical function of serotonin signaling in regulating actomyosin contractility and tissue flow reveals an ancestral role in morphogenesis of multicellular organisms.
    DOI:  https://doi.org/10.1038/s41467-023-41178-w
  46. Sci Transl Med. 2023 Sep 06. 15(712): eadh0380
    Stem-like CD4+ T cells in perivascular tertiary lymphoid structures sustain autoimmune vasculitis.
    Yuki Sato, Abhinav Jain, Shozo Ohtsuki, Hirohisa Okuyama, Ines Sturmlechner, Yoshinori Takashima, Kevin-Phu C Le, Melanie C Bois, Gerald J Berry, Kenneth J Warrington, Jörg J Goronzy, Cornelia M Weyand.
      Autoimmune vasculitis of the medium and large elastic arteries can cause blindness, stroke, aortic arch syndrome, and aortic aneurysm. The disease is often refractory to immunosuppressive therapy and progresses over decades as smoldering aortitis. How the granulomatous infiltrates in the vessel wall are maintained and how tissue-infiltrating T cells and macrophages are replenished are unknown. Single-cell and whole-tissue transcriptomic studies of immune cell populations in vasculitic arteries identified a CD4+ T cell population with stem cell-like features. CD4+ T cells supplying the tissue-infiltrating and tissue-damaging effector T cells survived in tertiary lymphoid structures around adventitial vasa vasora, expressed the transcription factor T cell factor 1 (TCF1), had high proliferative potential, and gave rise to two effector populations, Eomesodermin (EOMES)+ cytotoxic T cells and B cell lymphoma 6 (BCL6)+ T follicular helper-like cells. TCF1hiCD4+ T cells expressing the interleukin 7 receptor (IL-7R) sustained vasculitis in serial transplantation experiments. Thus, TCF1hiCD4+ T cells function as disease stem cells and promote chronicity and autonomy of autoimmune tissue inflammation. Remission-inducing therapies will require targeting stem-like CD4+ T cells instead of only effector T cells.
    DOI:  https://doi.org/10.1126/scitranslmed.adh0380
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