bims-nimamd Biomed News
on Neuroimmunity and neuroinflammation in ageing and metabolic disease
Issue of 2022–12–11
fifty-four papers selected by
Fawaz Alzaïd, Sorbonne Université
  1. Maturation and specialization of group 2 innate lymphoid cells through the lung-gut axis.
  2. Whole genome sequencing identifies structural variants contributing to hematologic traits in the NHLBI TOPMed program.
  3. Not so neutral lipids: Metabolic regulation of the pre-metastatic niche.
  4. Limited conservation in cross-species comparison of GLK transcription factor binding suggested wide-spread cistrome divergence.
  5. Autoimmunity-associated T cell receptors recognize HLA-B*27-bound peptides.
  6. A versatile functional assay for genetic variants in human disease.
  7. Human height-associated variants.
  8. A conserved population of MHC II-restricted, innate-like, commensal-reactive T cells in the gut of humans and mice.
  9. Deconstruction of a hypothalamic astrocyte-white adipocyte sympathetic axis that regulates lipolysis in mice.
  10. Intracellular galectin-3 is a lipopolysaccharide sensor that promotes glycolysis through mTORC1 activation.
  11. Age-associated remodeling of T cell immunity and metabolism.
  12. SARS-CoV-2 Spike triggers barrier dysfunction and vascular leak via integrins and TGF-β signaling.
  13. SESAME-catalyzed H3T11 phosphorylation inhibits Dot1-catalyzed H3K79me3 to regulate autophagy and telomere silencing.
  14. Parvalbumin basket cell myelination accumulates axonal mitochondria to internodes.
  15. Epiregulin is a dendritic cell-derived EGFR ligand that maintains skin and lung fibrosis.
  16. Setd2 supports GATA3+ST2+ thymic-derived Treg cells and suppresses intestinal inflammation.
  17. Breast cancer prevention by short-term inhibition of TGFβ signaling.
  18. Cutting Edge: mTORC2 Regulates CD8+ Effector and Memory T Cell Differentiation through Serum and Glucocorticoid Kinase 1.
  19. Recruitment of CTCF to an Fto enhancer is responsible for transgenerational inheritance of BPA-induced obesity.
  20. A framework for clinical cancer subtyping from nucleosome profiling of cell-free DNA.
  21. Extracellular traps from activated vascular smooth muscle cells drive the progression of atherosclerosis.
  22. GPR174 knockdown enhances blood flow recovery in hindlimb ischemia mice model by upregulating AREG expression.
  23. The dynamic clustering of insulin receptor underlies its signaling and is disrupted in insulin resistance.
  24. DAP5 enables main ORF translation on mRNAs with structured and uORF-containing 5' leaders.
  25. Usp22 is an intracellular regulator of systemic emergency hematopoiesis.
  26. Discovery and systematic characterization of risk variants and genes for coronary artery disease in over a million participants.
  27. Fatty acids derived from the probiotic Lacticaseibacillus rhamnosus HA-114 suppress age-dependent neurodegeneration.
  28. Identification of human progenitors of exhausted CD8+ T cells associated with elevated IFN-γ response in early phase of viral infection.
  29. KLF4-PFKFB3-driven glycolysis is essential for phenotypic switching of vascular smooth muscle cells.
  30. Functional proteomic profiling links deficient DNA clearance with increased mortality in individuals with severe COVID-19 pneumonia.
  31. Differential IL18 signaling via IL18 receptor and Na-Cl co-transporter discriminating thermogenesis and glucose metabolism regulation.
  32. High-throughput robust single-cell DNA methylation profiling with sciMETv2.
  33. Membrane curvature governs the distribution of Piezo1 in live cells.
  34. Divergent self-association properties of paralogous proteins TRIM2 and TRIM3 regulate their E3 ligase activity.
  35. The deubiquitinating enzyme complex BRISC regulates Aurora B activation via lysine-63-linked ubiquitination in mitosis.
  36. Cryo-EM structure of ssDNA bacteriophage ΦCjT23 provides insight into early virus evolution.
  37. Langerhans cells are essential components of the angiogenic niche during murine skin repair.
  38. Community voices: broadening participation in Science, Technology, Engineering, Mathematics, and Medicine among persons with disabilities.
  39. An in silico method to assess antibody fragment polyreactivity.
  40. Genetic features and therapeutic relevance of emergent circulating tumor DNA alterations in refractory non-colorectal gastrointestinal cancers.
  41. Next generation genetically encoded fluorescent sensors for serotonin.
  42. Principles of mitoribosomal small subunit assembly in eukaryotes.
  43. Why is strep A surging - and how worried are scientists?
  44. Evidence that direct inhibition of transcription factor binding is the prevailing mode of gene and repeat repression by DNA methylation.
  45. How smallpox inoculation united America.
  46. Dual communities in spatial networks.
  47. Mechanistic target of rapamycin complex 1 orchestrates the interplay between hepatocytes and Kupffer cells to determine the outcome of immune-mediated hepatitis.
  48. A metabolic associated fatty liver disease risk variant in MBOAT7 regulates toll like receptor induced outcomes.
  49. Meteorin-like is an injectable peptide that can enhance regeneration in aged muscle through immune-driven fibro/adipogenic progenitor signaling.
  50. Retrotransposon instability dominates the acquired mutation landscape of mouse induced pluripotent stem cells.
  51. Noradrenergic signaling mediates cortical early tagging and storage of remote memory.
  52. LDL delivery of microbial small RNAs drives atherosclerosis through macrophage TLR8.
  53. Visualizing the transiently populated closed-state of human HSP90 ATP binding domain.
  54. Multiple drivers and lineage-specific insect extinctions during the Permo-Triassic.
  1. Nat Commun. 2022 Dec 09. 13(1): 7600
    Maturation and specialization of group 2 innate lymphoid cells through the lung-gut axis.
    Min Zhao, Fei Shao, Dou Yu, Jiaqi Zhang, Zhen Liu, Jiangwen Ma, Pengyan Xia, Shuo Wang.
      Innate lymphoid cells (ILC) are abundant in mucosal tissues. They serve critical functions in anti-pathogen response and tissue homeostasis. However, the heterogenous composition of ILCs in mucosal sites and their various maturation trajectories are less well known. In this study, we characterize ILC types and functions from both the lung and the small intestine, and identify their tissue-specific markers. We find that ILC2s residing in the lung express CCR2, whereas intestinal ILC2s express CCR4. Through the use of CCR2 and CCR4 reporter mice, we show that ILC2s undergo translocation via the lung-gut axis upon IL-33 treatment. This trajectory of ILC2s is also observed at the postnatal stage. Allergen-induced activation of lung ILC2s affects the homeostasis of gut ILC2s. Together, our findings implicate that ILCs display tissue-specific features in both the lung and gut, and ILC2s mature along the lung-gut axis in particular homeostatic and inflammatory conditions.
    DOI:  https://doi.org/10.1038/s41467-022-35347-6
  2. Nat Commun. 2022 Dec 08. 13(1): 7592
    Whole genome sequencing identifies structural variants contributing to hematologic traits in the NHLBI TOPMed program.
    Marsha M Wheeler, Adrienne M Stilp, Shuquan Rao, Bjarni V Halldórsson, Doruk Beyter, Jia Wen, Anna V Mihkaylova, Caitlin P McHugh, John Lane, Min-Zhi Jiang, Laura M Raffield, Goo Jun, Fritz J Sedlazeck, Ginger Metcalf, Yao Yao, Joshua B Bis, Nathalie Chami, Paul S de Vries, Pinkal Desai, James S Floyd, Yan Gao, Kai Kammers, Wonji Kim, Jee-Young Moon, Aakrosh Ratan, Lisa R Yanek, Laura Almasy, Lewis C Becker, John Blangero, Michael H Cho, Joanne E Curran, Myriam Fornage, Robert C Kaplan, Joshua P Lewis, Ruth J F Loos, Braxton D Mitchell, Alanna C Morrison, Michael Preuss, Bruce M Psaty, Stephen S Rich, Jerome I Rotter, Hua Tang, Russell P Tracy, Eric Boerwinkle, Goncalo R Abecasis, Thomas W Blackwell, Albert V Smith, Andrew D Johnson, Rasika A Mathias, Deborah A Nickerson, Matthew P Conomos, Yun Li, Unnur Þorsteinsdóttir, Magnús K Magnússon, Kari Stefansson, Nathan D Pankratz, Daniel E Bauer, Paul L Auer, Alex P Reiner.
      Genome-wide association studies have identified thousands of single nucleotide variants and small indels that contribute to variation in hematologic traits. While structural variants are known to cause rare blood or hematopoietic disorders, the genome-wide contribution of structural variants to quantitative blood cell trait variation is unknown. Here we utilized whole genome sequencing data in ancestrally diverse participants of the NHLBI Trans Omics for Precision Medicine program (N = 50,675) to detect structural variants associated with hematologic traits. Using single variant tests, we assessed the association of common and rare structural variants with red cell-, white cell-, and platelet-related quantitative traits and observed 21 independent signals (12 common and 9 rare) reaching genome-wide significance. The majority of these associations (N = 18) replicated in independent datasets. In genome-editing experiments, we provide evidence that a deletion associated with lower monocyte counts leads to disruption of an S1PR3 monocyte enhancer and decreased S1PR3 expression.
    DOI:  https://doi.org/10.1038/s41467-022-35354-7
  3. Cell Metab. 2022 Dec 06. pii: S1550-4131(22)00498-3. [Epub ahead of print]34(12): 1899-1900
    Not so neutral lipids: Metabolic regulation of the pre-metastatic niche.
    Joshua D Schoenfeld, Santosha A Vardhana.
      How primary tumors alter distant tissue sites to facilitate seeding and metastasis remains unclear. In this issue, Gong et al. demonstrate that IL-1β-dependent lipid accumulation in lung mesenchymal cells supports both tumor growth and NK cell dysfunction, facilitating lung metastasis of primary breast tumors.
    DOI:  https://doi.org/10.1016/j.cmet.2022.11.007
  4. Nat Commun. 2022 Dec 09. 13(1): 7632
    Limited conservation in cross-species comparison of GLK transcription factor binding suggested wide-spread cistrome divergence.
    Xiaoyu Tu, Sibo Ren, Wei Shen, Jianjian Li, Yuxiang Li, Chuanshun Li, Yangmeihui Li, Zhanxiang Zong, Weibo Xie, Donald Grierson, Zhangjun Fei, Jim Giovannoni, Pinghua Li, Silin Zhong.
      Non-coding cis-regulatory variants in animal genomes are an important driving force in the evolution of transcription regulation and phenotype diversity. However, cistrome dynamics in plants remain largely underexplored. Here, we compare the binding of GOLDEN2-LIKE (GLK) transcription factors in tomato, tobacco, Arabidopsis, maize and rice. Although the function of GLKs is conserved, most of their binding sites are species-specific. Conserved binding sites are often found near photosynthetic genes dependent on GLK for expression, but sites near non-differentially expressed genes in the glk mutant are nevertheless under purifying selection. The binding sites' regulatory potential can be predicted by machine learning model using quantitative genome features and TF co-binding information. Our study show that genome cis-variation caused wide-spread TF binding divergence, and most of the TF binding sites are genetically redundant. This poses a major challenge for interpreting the effect of individual sites and highlights the importance of quantitatively measuring TF occupancy.
    DOI:  https://doi.org/10.1038/s41467-022-35438-4
  5. Nature. 2022 Dec 07.
    Autoimmunity-associated T cell receptors recognize HLA-B*27-bound peptides.
    Xinbo Yang, Lee I Garner, Ivan V Zvyagin, Michael A Paley, Ekaterina A Komech, Kevin M Jude, Xiang Zhao, Ricardo A Fernandes, Lynn M Hassman, Grace L Paley, Christina S Savvides, Simon Brackenridge, Max N Quastel, Dmitriy M Chudakov, Paul Bowness, Wayne M Yokoyama, Andrew J McMichael, Geraldine M Gillespie, K Christopher Garcia.
      Human leucocyte antigen B*27 (HLA-B*27) is strongly associated with inflammatory diseases of the spine and pelvis (for example, ankylosing spondylitis (AS)) and the eye (that is, acute anterior uveitis (AAU))1. How HLA-B*27 facilitates disease remains unknown, but one possible mechanism could involve presentation of pathogenic peptides to CD8+ T cells. Here we isolated orphan T cell receptors (TCRs) expressing a disease-associated public β-chain variable region-complementary-determining region 3β (BV9-CDR3β) motif2-4 from blood and synovial fluid T cells from individuals with AS and from the eye in individuals with AAU. These TCRs showed consistent α-chain variable region (AV21) chain pairing and were clonally expanded in the joint and eye. We used HLA-B*27:05 yeast display peptide libraries to identify shared self-peptides and microbial peptides that activated the AS- and AAU-derived TCRs. Structural analysis revealed that TCR cross-reactivity for peptide-MHC was rooted in a shared binding motif present in both self-antigens and microbial antigens that engages the BV9-CDR3β TCRs. These findings support the hypothesis that microbial antigens and self-antigens could play a pathogenic role in HLA-B*27-associated disease.
    DOI:  https://doi.org/10.1038/s41586-022-05501-7
  6. Nat Genet. 2022 Dec;54(12): 1778-1779
    A versatile functional assay for genetic variants in human disease.
      
    DOI:  https://doi.org/10.1038/s41588-022-01226-5
  7. Nat Genet. 2022 Dec;54(12): 1764
    Human height-associated variants.
    Wei Li.
      
    DOI:  https://doi.org/10.1038/s41588-022-01263-0
  8. Nat Commun. 2022 Dec 03. 13(1): 7472
    A conserved population of MHC II-restricted, innate-like, commensal-reactive T cells in the gut of humans and mice.
    Carl-Philipp Hackstein, Dana Costigan, Linnea Drexhage, Claire Pearson, Samuel Bullers, Nicholas Ilott, Hossain Delowar Akther, Yisu Gu, Michael E B FitzPatrick, Oliver J Harrison, Lucy C Garner, Elizabeth H Mann, Sumeet Pandey, Matthias Friedrich, Nicholas M Provine, Holm H Uhlig, Emanuele Marchi, Fiona Powrie, Paul Klenerman, Emily E Thornton.
      Interactions with commensal microbes shape host immunity on multiple levels and play a pivotal role in human health and disease. Tissue-dwelling, antigen-specific T cells are poised to respond to local insults, making their phenotype important in the relationship between host and microbes. Here we show that MHC-II restricted, commensal-reactive T cells in the colon of both humans and mice acquire transcriptional and functional characteristics associated with innate-like T cells. This cell population is abundant and conserved in the human and murine colon and endowed with polyfunctional effector properties spanning classic Th1- and Th17-cytokines, cytotoxic molecules, and regulators of epithelial homeostasis. T cells with this phenotype are increased in ulcerative colitis patients, and their presence aggravates pathology in dextran sodium sulphate-treated mice, pointing towards a pathogenic role in colitis. Our findings add to the expanding spectrum of innate-like immune cells positioned at the frontline of intestinal immune surveillance, capable of acting as sentinels of microbes and the local cytokine milieu.
    DOI:  https://doi.org/10.1038/s41467-022-35126-3
  9. Nat Commun. 2022 Dec 07. 13(1): 7536
    Deconstruction of a hypothalamic astrocyte-white adipocyte sympathetic axis that regulates lipolysis in mice.
    Dan Chen, Yong Qi, Jia Zhang, Yunlei Yang.
      The role of non-neuronal glial cells in the regulation of adipose sympathetic nerve activity and adipocyte functions such as white adipose tissue lipid lipolysis is poorly understood. Here, we combine chemo/optogenetic manipulations of medio-basal hypothalamic astrocytes, real-time fiber photometry monitoring of white adipose tissue norepinephrine (NE) contents and nerve activities, electrophysiological recordings of local sympathetic inputs to inguinal white adipose tissue (iWAT), and adipose tissue lipid lipolytic assays to define the functional roles of hypothalamic astrocytes in the regulation of iWAT sympathetic outflow and lipolysis. Our results show that astrocyte stimulation elevates iWAT NE contents, excites sympathetic neural inputs and promotes lipolysis. Mechanistically, we find that sympathetic paravertebral ganglia (PG) partake in those astrocyte effects. We also find that astrocyte stimulation excites pro-opiomelanocortin (POMC) neurons in the arcuate nucleus of the hypothalamus (ARH), and chemogenetic inhibition of POMC neurons blunts the effects induced by astrocyte stimulation. While we cannot exclude potential roles played by other cell populations such as microglia, our findings in this study reveal a central astrocyte-peripheral adipocyte axis modulating sympathetic drive to adipose tissues and adipocyte functions, one that might serve as a target for therapeutic intervention in the treatment of obesity.
    DOI:  https://doi.org/10.1038/s41467-022-35258-6
  10. Nat Commun. 2022 Dec 08. 13(1): 7578
    Intracellular galectin-3 is a lipopolysaccharide sensor that promotes glycolysis through mTORC1 activation.
    Xing Chen, Chunyu Yu, Xinhua Liu, Beibei Liu, Xiaodi Wu, Jiajing Wu, Dong Yan, Lulu Han, Zifan Tang, Xinyi Yuan, Jianqiu Wang, Yue Wang, Shumeng Liu, Lin Shan, Yongfeng Shang.
      How the carbohydrate binding protein galectin-3 might act as a diabetogenic and tumorogenic factor remains to be investigated. Here we report that intracellular galectin-3 interacts with Rag GTPases and Ragulator on lysosomes. We show that galectin-3 senses lipopolysaccharide (LPS) to facilitate the interaction of Rag GTPases and Ragulator, leading to the activation of mTORC1. We find that the lipopolysaccharide/galectin-3-Rag GTPases/Ragulator-mTORC1 axis regulates a cohort of genes including GLUT1, and HK2, and PKM2 that are critically involved in glucose uptake and glycolysis. Indeed, galectin-3 deficiency severely compromises LPS-promoted glycolysis. Importantly, the expression of HK2 is significantly reduced in diabetes patients. In multiple types of cancer including hepatocellular carcinoma (HCC), galectin-3 is highly expressed, and its level of expression is positively correlated with that of HK2 and PKM2 and negatively correlated with the prognosis of HCC patients. Our study unravels that galectin-3 is a sensor of LPS, an important modulator of the mTORC1 signaling, and a critical regulator of glucose metabolism.
    DOI:  https://doi.org/10.1038/s41467-022-35334-x
  11. Cell Metab. 2022 Nov 29. pii: S1550-4131(22)00496-X. [Epub ahead of print]
    Age-associated remodeling of T cell immunity and metabolism.
    SeongJun Han, Peter Georgiev, Alison E Ringel, Arlene H Sharpe, Marcia C Haigis.
      Aging results in remodeling of T cell immunity and is associated with poor clinical outcomes in age-related diseases such as cancer. Among the hallmarks of aging, changes in host and cellular metabolism critically affect the development, maintenance, and function of T cells. Although metabolic perturbations impact anti-tumor T cell responses, the link between age-associated metabolic dysfunction and anti-tumor immunity remains unclear. In this review, we summarize recent advances in our understanding of aged T cell metabolism, with a focus on the bioenergetic and immunologic features of T cell subsets unique to the aging process. We also survey insights into mechanisms of metabolic T cell dysfunction in aging and discuss the impacts of aging on the efficacy of cancer immunotherapy. As the average life expectancy continues to increase, understanding the interplay between age-related metabolic reprogramming and maladaptive T cell immunity will be instrumental for the development of therapeutic strategies for older patients.
    Keywords:  T cells; aging; cancer; immunity; immunotherapy; metabolism; mitochondria
    DOI:  https://doi.org/10.1016/j.cmet.2022.11.005
  12. Nat Commun. 2022 Dec 09. 13(1): 7630
    SARS-CoV-2 Spike triggers barrier dysfunction and vascular leak via integrins and TGF-β signaling.
    Scott B Biering, Francielle Tramontini Gomes de Sousa, Laurentia V Tjang, Felix Pahmeier, Chi Zhu, Richard Ruan, Sophie F Blanc, Trishna S Patel, Caroline M Worthington, Dustin R Glasner, Bryan Castillo-Rojas, Venice Servellita, Nicholas T N Lo, Marcus P Wong, Colin M Warnes, Daniel R Sandoval, Thomas Mandel Clausen, Yale A Santos, Douglas M Fox, Victoria Ortega, Anders M Näär, Ralph S Baric, Sarah A Stanley, Hector C Aguilar, Jeffrey D Esko, Charles Y Chiu, John E Pak, P Robert Beatty, Eva Harris.
      Severe COVID-19 is associated with epithelial and endothelial barrier dysfunction within the lung as well as in distal organs. While it is appreciated that an exaggerated inflammatory response is associated with barrier dysfunction, the triggers of vascular leak are unclear. Here, we report that cell-intrinsic interactions between the Spike (S) glycoprotein of SARS-CoV-2 and epithelial/endothelial cells are sufficient to induce barrier dysfunction in vitro and vascular leak in vivo, independently of viral replication and the ACE2 receptor. We identify an S-triggered transcriptional response associated with extracellular matrix reorganization and TGF-β signaling. Using genetic knockouts and specific inhibitors, we demonstrate that glycosaminoglycans, integrins, and the TGF-β signaling axis are required for S-mediated barrier dysfunction. Notably, we show that SARS-CoV-2 infection caused leak in vivo, which was reduced by inhibiting integrins. Our findings offer mechanistic insight into SARS-CoV-2-triggered vascular leak, providing a starting point for development of therapies targeting COVID-19.
    DOI:  https://doi.org/10.1038/s41467-022-34910-5
  13. Nat Commun. 2022 Dec 06. 13(1): 7526
    SESAME-catalyzed H3T11 phosphorylation inhibits Dot1-catalyzed H3K79me3 to regulate autophagy and telomere silencing.
    Fei He, Qi Yu, Min Wang, Rongsha Wang, Xuanyunjing Gong, Feng Ge, Xilan Yu, Shanshan Li.
      The glycolytic enzyme, pyruvate kinase Pyk1 maintains telomere heterochromatin by phosphorylating histone H3T11 (H3pT11), which promotes SIR (silent information regulator) complex binding at telomeres and prevents autophagy-mediated Sir2 degradation. However, the exact mechanism of action for H3pT11 is poorly understood. Here, we report that H3pT11 directly inhibits Dot1-catalyzed H3K79 tri-methylation (H3K79me3) and uncover how this histone crosstalk regulates autophagy and telomere silencing. Mechanistically, Pyk1-catalyzed H3pT11 directly reduces the binding of Dot1 to chromatin and inhibits Dot1-catalyzed H3K79me3, which leads to transcriptional repression of autophagy genes and reduced autophagy. Despite the antagonism between H3pT11 and H3K79me3, they work together to promote the binding of SIR complex at telomeres to maintain telomere silencing. Furthermore, we identify Reb1 as a telomere-associated factor that recruits Pyk1-containing SESAME (Serine-responsive SAM-containing Metabolic Enzyme) complex to telomere regions to phosphorylate H3T11 and prevent the invasion of H3K79me3 from euchromatin into heterochromatin to maintain telomere silencing. Together, these results uncover a histone crosstalk and provide insights into dynamic regulation of silent heterochromatin and autophagy in response to cell metabolism.
    DOI:  https://doi.org/10.1038/s41467-022-35182-9
  14. Nat Commun. 2022 Dec 09. 13(1): 7598
    Parvalbumin basket cell myelination accumulates axonal mitochondria to internodes.
    Koen Kole, Bas J B Voesenek, Maria E Brinia, Naomi Petersen, Maarten H P Kole.
      Parvalbumin-expressing (PV+) basket cells are fast-spiking inhibitory interneurons that exert critical control over local circuit activity and oscillations. PV+ axons are often myelinated, but the electrical and metabolic roles of interneuron myelination remain poorly understood. Here, we developed viral constructs allowing cell type-specific investigation of mitochondria with genetically encoded fluorescent probes. Single-cell reconstructions revealed that mitochondria selectively cluster to myelinated segments of PV+ basket cells, confirmed by analyses of a high-resolution electron microscopy dataset. In contrast to the increased mitochondrial densities in excitatory axons cuprizone-induced demyelination abolished mitochondrial clustering in PV+ axons. Furthermore, with genetic deletion of myelin basic protein the mitochondrial clustering was still observed at internodes wrapped by noncompacted myelin, indicating that compaction is dispensable. Finally, two-photon imaging of action potential-evoked calcium (Ca2+) responses showed that interneuron myelination attenuates both the cytosolic and mitochondrial Ca2+ transients. These findings suggest that oligodendrocyte ensheathment of PV+ axons assembles mitochondria to branch selectively fine-tune metabolic demands.
    DOI:  https://doi.org/10.1038/s41467-022-35350-x
  15. Sci Immunol. 2022 Dec 16. 7(78): eabq6691
    Epiregulin is a dendritic cell-derived EGFR ligand that maintains skin and lung fibrosis.
    Ian D Odell, Holly Steach, Stephen B Gauld, Lauren Reinke-Breen, Jozsef Karman, Tracy L Carr, Joseph B Wetter, Lucy Phillips, Monique Hinchcliff, Richard A Flavell.
      Immune cells are fundamental regulators of extracellular matrix (ECM) production by fibroblasts and have important roles in determining extent of fibrosis in response to inflammation. Although much is known about fibroblast signaling in fibrosis, the molecular signals between immune cells and fibroblasts that drive its persistence are poorly understood. We therefore analyzed skin and lung samples of patients with diffuse cutaneous systemic sclerosis, an autoimmune disease that causes debilitating fibrosis of the skin and internal organs. Here, we define a critical role of epiregulin-EGFR signaling between dendritic cells and fibroblasts to maintain elevated ECM production and accumulation in fibrotic tissue. We found that epiregulin expression marks an inducible state of DC3 dendritic cells triggered by type I interferon and that DC3-derived epiregulin activates EGFR on fibroblasts, driving a positive feedback loop through NOTCH signaling. In mouse models of skin and lung fibrosis, epiregulin was essential for persistence of fibrosis in both tissues, which could be abrogated by epiregulin genetic deficiency or a neutralizing antibody. Therapeutic administration of epiregulin antibody reversed fibrosis in patient skin and lung explants, identifying it as a previously unexplored biologic drug target. Our findings reveal epiregulin as a crucial immune signal that maintains skin and lung fibrosis in multiple diseases and represents a promising antifibrotic target.
    DOI:  https://doi.org/10.1126/sciimmunol.abq6691
  16. Nat Commun. 2022 Dec 03. 13(1): 7468
    Setd2 supports GATA3+ST2+ thymic-derived Treg cells and suppresses intestinal inflammation.
    Zhaoyun Ding, Ting Cai, Jupei Tang, Hanxiao Sun, Xinyi Qi, Yunpeng Zhang, Yan Ji, Liyun Yuan, Huidan Chang, Yanhui Ma, Hong Zhou, Li Li, Huiming Sheng, Ju Qiu.
      Treg cells acquire distinct transcriptional properties to suppress specific inflammatory responses. Transcription characteristics of Treg cells are regulated by epigenetic modifications, the mechanism of which remains obscure. Here, we report that Setd2, a histone H3K36 methyltransferase, is important for the survival and suppressive function of Treg cells, especially those from the intestine. Setd2 supports GATA3+ST2+ intestinal thymic-derived Treg (tTreg) cells by facilitating the expression and reciprocal relationship of GATA3 and ST2 in tTreg cells. IL-33 preferentially boosts Th2 cells rather than GATA3+ Treg cells in Foxp3Cre-YFPSetd2 flox/flox mice, corroborating the constraint of Th2 responses by Setd2 expression in Treg cells. SETD2 sustains GATA3 expression in human Treg cells, and SETD2 expression is increased in Treg cells from human colorectal cancer tissues. Epigenetically, Setd2 regulates the transcription of target genes (including Il1rl1) by modulating the activity of promoters and intragenic enhancers where H3K36me3 is typically deposited. Our findings provide mechanistic insights into the regulation of Treg cells and intestinal immunity by Setd2.
    DOI:  https://doi.org/10.1038/s41467-022-35250-0
  17. Nat Commun. 2022 Dec 07. 13(1): 7558
    Breast cancer prevention by short-term inhibition of TGFβ signaling.
    Maša Alečković, Simona Cristea, Carlos R Gil Del Alcazar, Pengze Yan, Lina Ding, Ethan D Krop, Nicholas W Harper, Ernesto Rojas Jimenez, Donghao Lu, Anushree C Gulvady, Pierre Foidart, Marco Seehawer, Benedetto Diciaccio, Katherine C Murphy, Jason Pyrdol, Jayati Anand, Kodie Garza, Kai W Wucherpfennig, Rulla M Tamimi, Franziska Michor, Kornelia Polyak.
      Cancer prevention has a profound impact on cancer-associated mortality and morbidity. We previously identified TGFβ signaling as a candidate regulator of mammary epithelial cells associated with breast cancer risk. Here, we show that short-term TGFBR inhibitor (TGFBRi) treatment of peripubertal ACI inbred and Sprague Dawley outbred rats induces lasting changes and prevents estrogen- and carcinogen-induced mammary tumors, respectively. We identify TGFBRi-responsive cell populations by single cell RNA-sequencing, including a unique epithelial subpopulation designated secretory basal cells (SBCs) with progenitor features. We detect SBCs in normal human breast tissues and find them to be associated with breast cancer risk. Interactome analysis identifies SBCs as the most interactive cell population and the main source of insulin-IGF signaling. Accordingly, inhibition of TGFBR and IGF1R decrease proliferation of organoid cultures. Our results reveal a critical role for TGFβ in regulating mammary epithelial cells relevant to breast cancer and serve as a proof-of-principle cancer prevention strategy.
    DOI:  https://doi.org/10.1038/s41467-022-35043-5
  18. J Immunol. 2022 Dec 15. 209(12): 2287-2291
    Cutting Edge: mTORC2 Regulates CD8+ Effector and Memory T Cell Differentiation through Serum and Glucocorticoid Kinase 1.
    Chirag H Patel, Emily B Heikamp, Wei Xu, Im-Hong Sun, Min-Hee Oh, Im-Meng Sun, Jiayu Wen, Ada J Tam, Richard L Blosser, Jonathan D Powell.
      The mechanistic target of rapamycin is an essential regulator of T cell metabolism and differentiation. In this study, we demonstrate that serum- and glucocorticoid-regulated kinase 1 (SGK1), a downstream node of mechanistic target of rapamycin complex 2 signaling, represses memory CD8+ T cell differentiation. During acute infections, murine SGK1-deficient CD8+ T cells adopt an early memory precursor phenotype leading to more long-lived memory T cells. Thus, SGK1-deficient CD8+ T cells demonstrate an enhanced recall capacity in response to reinfection and can readily reject tumors. Mechanistically, activation of SGK1-deficient CD8+ T cells results in decreased Foxo1 phosphorylation and increased nuclear translocation of Foxo1 to promote early memory development. Overall, SGK1 might prove to be a powerful target for enhancing the efficacy of vaccines and tumor immunotherapy.
    DOI:  https://doi.org/10.4049/jimmunol.2100669
  19. Proc Natl Acad Sci U S A. 2022 12 13. 119(50): e2214988119
    Recruitment of CTCF to an Fto enhancer is responsible for transgenerational inheritance of BPA-induced obesity.
    Yoon Hee Jung, Hsiao-Lin V Wang, Daniel Ruiz, Brianna J Bixler, Hannah Linsenbaum, Jian-Feng Xiang, Samantha Forestier, Andrew M Shafik, Peng Jin, Victor G Corces.
      The mechanisms by which environmentally-induced epiphenotypes are transmitted transgenerationally in mammals are poorly understood. Here we show that exposure of pregnant mouse females to bisphenol A (BPA) results in obesity in the F2 progeny due to increased food intake. This epiphenotype can be transmitted up to the F6 generation. Analysis of chromatin accessibility in sperm of the F1-F6 generations reveals alterations at sites containing binding motifs for CCCTC-binding factor (CTCF) at two cis-regulatory elements (CREs) of the Fto gene that correlate with transmission of obesity. These CREs show increased interactions in sperm of obese mice with the Irx3 and Irx5 genes, which are involved in the differentiation of appetite-controlling neurons. Deletion of the CTCF site in Fto results in mice that have normal food intake and fail to become obese when ancestrally exposed to BPA. The results suggest that epigenetic alterations of Fto can lead to the same phenotypes as genetic variants.
    Keywords:  chromatin; fertilization; oocyte; sperm; transcription
    DOI:  https://doi.org/10.1073/pnas.2214988119
  20. Nat Commun. 2022 Dec 03. 13(1): 7475
    A framework for clinical cancer subtyping from nucleosome profiling of cell-free DNA.
    Anna-Lisa Doebley, Minjeong Ko, Hanna Liao, A Eden Cruikshank, Katheryn Santos, Caroline Kikawa, Joseph B Hiatt, Robert D Patton, Navonil De Sarkar, Katharine A Collier, Anna C H Hoge, Katharine Chen, Anat Zimmer, Zachary T Weber, Mohamed Adil, Jonathan B Reichel, Paz Polak, Viktor A Adalsteinsson, Peter S Nelson, David MacPherson, Heather A Parsons, Daniel G Stover, Gavin Ha.
      Cell-free DNA (cfDNA) has the potential to inform tumor subtype classification and help guide clinical precision oncology. Here we develop Griffin, a framework for profiling nucleosome protection and accessibility from cfDNA to study the phenotype of tumors using as low as 0.1x coverage whole genome sequencing data. Griffin employs a GC correction procedure tailored to variable cfDNA fragment sizes, which generates a better representation of chromatin accessibility and improves the accuracy of cancer detection and tumor subtype classification. We demonstrate estrogen receptor subtyping from cfDNA in metastatic breast cancer. We predict estrogen receptor subtype in 139 patients with at least 5% detectable circulating tumor DNA with an area under the receive operator characteristic curve (AUC) of 0.89 and validate performance in independent cohorts (AUC = 0.96). In summary, Griffin is a framework for accurate tumor subtyping and can be generalizable to other cancer types for precision oncology applications.
    DOI:  https://doi.org/10.1038/s41467-022-35076-w
  21. Nat Commun. 2022 Dec 06. 13(1): 7500
    Extracellular traps from activated vascular smooth muscle cells drive the progression of atherosclerosis.
    Ming Zhai, Shiyu Gong, Peipei Luan, Yefei Shi, Wenxin Kou, Yanxi Zeng, Jiayun Shi, Guanye Yu, Jiayun Hou, Qing Yu, Weixia Jian, Jianhui Zhuang, Mark W Feinberg, Wenhui Peng.
      Extracellular DNA traps (ETs) represent an immune response by which cells release essential materials like chromatin and granular proteins. Previous studies have demonstrated that the transdifferentiation of vascular smooth muscle cells (VSMCs) plays a crucial role in atherosclerosis. This study seeks to investigate the interaction between CD68+ VSMCs and the formation of ETs and highlight its function in atherosclerosis. Here we show that ETs are inhibited, and atherosclerotic plaque formation is alleviated in male Myh11CrePad4flox/flox mice undergoing an adeno-associated-virus-8 (AAV8) mediating overexpression of proprotein convertase subtilisin/kexin type 9 mutation (PCSK9) injection and being challenged with a high-fat diet. Obvious ETs generated from CD68+ VSMCs are inhibited by Cl-amidine and DNase I in vitro. By utilizing VSMCs-lineage tracing technology and single-cell RNA sequencing (scRNA-seq), we demonstrate that the ETs from CD68+ VSMCs influence the progress of atherosclerosis by regulating the direction of VSMCs' transdifferentiation through STING-SOCS1 or TLR4 signaling pathway.
    DOI:  https://doi.org/10.1038/s41467-022-35330-1
  22. Nat Commun. 2022 Dec 06. 13(1): 7519
    GPR174 knockdown enhances blood flow recovery in hindlimb ischemia mice model by upregulating AREG expression.
    Jin Liu, Lihong Pan, Wenxuan Hong, Siqin Chen, Peiyuan Bai, Wei Luo, Xiaolei Sun, Furong He, Xinlin Jia, Jialiang Cai, Yingjie Chen, Kai Hu, Zhenju Song, Junbo Ge, Aijun Sun.
      Regulatory T cells (Tregs) are critically involved in neovascularization, an important compensatory mechanism in peripheral artery disease. The contribution of G protein coupled receptor 174 (GPR174), which is a regulator of Treg function and development, in neovascularization remains elusive. Here, we show that genetic deletion of GPR174 in Tregs potentiated blood flow recovery in mice after hindlimb ischemia. GPR174 deficiency upregulates amphiregulin (AREG) expression in Tregs, thereby enhancing endothelial cell functions and reducing pro-inflammatory macrophage polarization and endothelial cell apoptosis. Mechanically, GPR174 regulates AREG expression by inhibiting the nuclear accumulation of early growth response protein 1 (EGR1) via Gαs/cAMP/PKA signal pathway activation. Collectively, these findings demonstrate that GPR174 negatively regulates angiogenesis and vascular remodeling in response to ischemic injury and that GPR174 may be a potential molecular target for therapeutic interventions of ischemic vascular diseases.
    DOI:  https://doi.org/10.1038/s41467-022-35159-8
  23. Nat Commun. 2022 Dec 06. 13(1): 7522
    The dynamic clustering of insulin receptor underlies its signaling and is disrupted in insulin resistance.
    Alessandra Dall'Agnese, Jesse M Platt, Ming M Zheng, Max Friesen, Giuseppe Dall'Agnese, Alyssa M Blaise, Jessica B Spinelli, Jonathan E Henninger, Erin N Tevonian, Nancy M Hannett, Charalampos Lazaris, Hannah K Drescher, Lea M Bartsch, Henry R Kilgore, Rudolf Jaenisch, Linda G Griffith, Ibrahim I Cisse, Jacob F Jeppesen, Tong I Lee, Richard A Young.
      Insulin receptor (IR) signaling is central to normal metabolic control and is dysregulated in metabolic diseases such as type 2 diabetes. We report here that IR is incorporated into dynamic clusters at the plasma membrane, in the cytoplasm and in the nucleus of human hepatocytes and adipocytes. Insulin stimulation promotes further incorporation of IR into these dynamic clusters in insulin-sensitive cells but not in insulin-resistant cells, where both IR accumulation and dynamic behavior are reduced. Treatment of insulin-resistant cells with metformin, a first-line drug used to treat type 2 diabetes, can rescue IR accumulation and the dynamic behavior of these clusters. This rescue is associated with metformin's role in reducing reactive oxygen species that interfere with normal dynamics. These results indicate that changes in the physico-mechanical features of IR clusters contribute to insulin resistance and have implications for improved therapeutic approaches.
    DOI:  https://doi.org/10.1038/s41467-022-35176-7
  24. Nat Commun. 2022 Dec 06. 13(1): 7510
    DAP5 enables main ORF translation on mRNAs with structured and uORF-containing 5' leaders.
    Ramona Weber, Leon Kleemann, Insa Hirschberg, Min-Yi Chung, Eugene Valkov, Cátia Igreja.
      Half of mammalian transcripts contain short upstream open reading frames (uORFs) that potentially regulate translation of the downstream coding sequence (CDS). The molecular mechanisms governing these events remain poorly understood. Here, we find that the non-canonical initiation factor Death-associated protein 5 (DAP5 or eIF4G2) is required for translation initiation on select transcripts. Using ribosome profiling and luciferase-based reporters coupled with mutational analysis we show that DAP5-mediated translation occurs on messenger RNAs (mRNAs) with long, structure-prone 5' leader sequences and persistent uORF translation. These mRNAs preferentially code for signalling factors such as kinases and phosphatases. We also report that cap/eIF4F- and eIF4A-dependent recruitment of DAP5 to the mRNA facilitates main CDS, but not uORF, translation suggesting a role for DAP5 in translation re-initiation. Our study reveals important mechanistic insights into how a non-canonical translation initiation factor involved in stem cell fate shapes the synthesis of specific signalling factors.
    DOI:  https://doi.org/10.1038/s41467-022-35019-5
  25. Sci Immunol. 2022 Dec 16. 7(78): eabq2061
    Usp22 is an intracellular regulator of systemic emergency hematopoiesis.
    Nikolaus Dietlein, Xi Wang, Jonas Metz, Olivier Disson, Fuwei Shang, Celine Beyersdörffer, Esther Rodríguez Correa, Daniel B Lipka, Yvonne Begus-Nahrmann, Robyn Laura Kosinsky, Steven A Johnsen, Marc Lecuit, Thomas Höfer, Hans-Reimer Rodewald.
      Emergency hematopoiesis is a concerted response aimed toward enhanced protection from infection, involving multiple cell types and developmental stages across the immune system. Despite its importance, the underlying molecular regulation remains poorly understood. The deubiquitinase USP22 regulates the levels of monoubiquitinated histone H2B (H2Bub1), which is associated with activation of interferon responses upon viral infection. Here, we show that in the absence of infection or inflammation, mice lacking Usp22 in all hematopoietic cells display profound systemic emergency hematopoiesis, evident by increased hematopoietic stem cell proliferation, myeloid bias, and extramedullary hematopoiesis. Functionally, loss of Usp22 results in elevated phagocytosis by neutrophilic granulocytes and enhanced innate protection against Listeria monocytogenes infection. At the molecular level, we found this state of emergency hematopoiesis associated with transcriptional signatures of myeloid priming, enhanced mitochondrial respiration, and innate and adaptive immunity and inflammation. Augmented expression of many inflammatory genes was linked to elevated locus-specific H2Bub1 levels. Collectively, these results demonstrate the existence of a tunable epigenetic state that promotes systemic emergency hematopoiesis in a cell-autonomous manner to enhance innate protection, identifying potential paths toward immune enhancement.
    DOI:  https://doi.org/10.1126/sciimmunol.abq2061
  26. Nat Genet. 2022 Dec;54(12): 1803-1815
    Discovery and systematic characterization of risk variants and genes for coronary artery disease in over a million participants.
    Biobank Japan
      The discovery of genetic loci associated with complex diseases has outpaced the elucidation of mechanisms of disease pathogenesis. Here we conducted a genome-wide association study (GWAS) for coronary artery disease (CAD) comprising 181,522 cases among 1,165,690 participants of predominantly European ancestry. We detected 241 associations, including 30 new loci. Cross-ancestry meta-analysis with a Japanese GWAS yielded 38 additional new loci. We prioritized likely causal variants using functionally informed fine-mapping, yielding 42 associations with less than five variants in the 95% credible set. Similarity-based clustering suggested roles for early developmental processes, cell cycle signaling and vascular cell migration and proliferation in the pathogenesis of CAD. We prioritized 220 candidate causal genes, combining eight complementary approaches, including 123 supported by three or more approaches. Using CRISPR-Cas9, we experimentally validated the effect of an enhancer in MYO9B, which appears to mediate CAD risk by regulating vascular cell motility. Our analysis identifies and systematically characterizes >250 risk loci for CAD to inform experimental interrogation of putative causal mechanisms for CAD.
    DOI:  https://doi.org/10.1038/s41588-022-01233-6
  27. Commun Biol. 2022 Dec 07. 5(1): 1340
    Fatty acids derived from the probiotic Lacticaseibacillus rhamnosus HA-114 suppress age-dependent neurodegeneration.
    Audrey Labarre, Ericka Guitard, Gilles Tossing, Anik Forest, Eric Bareke, Marjorie Labrecque, Martine Tétreault, Matthieu Ruiz, J Alex Parker.
      The human microbiota is believed to influence health. Microbiome dysbiosis may be linked to neurological conditions like Alzheimer's disease, amyotrophic lateral sclerosis, and Huntington's disease. We report the ability of a probiotic bacterial strain in halting neurodegeneration phenotypes. We show that Lacticaseibacillus rhamnosus HA-114 is neuroprotective in C. elegans models of amyotrophic lateral sclerosis and Huntington's disease. Our results show that neuroprotection from L. rhamnosus HA-114 is unique from other L. rhamnosus strains and resides in its fatty acid content. Neuroprotection by L. rhamnosus HA-114 requires acdh-1/ACADSB, kat-1/ACAT1 and elo-6/ELOVL3/6, which are associated with fatty acid metabolism and mitochondrial β-oxidation. Our data suggest that disrupted lipid metabolism contributes to neurodegeneration and that dietary intervention with L. rhamnosus HA-114 restores lipid homeostasis and energy balance through mitochondrial β-oxidation. Our findings encourage the exploration of L. rhamnosus HA-114 derived interventions to modify the progression of neurodegenerative diseases.
    DOI:  https://doi.org/10.1038/s42003-022-04295-8
  28. Nat Commun. 2022 Dec 07. 13(1): 7543
    Identification of human progenitors of exhausted CD8+ T cells associated with elevated IFN-γ response in early phase of viral infection.
    Curtis Cai, Jerome Samir, Mehdi R Pirozyan, Thiruni N Adikari, Money Gupta, Preston Leung, Brendan Hughes, Willem Van der Byl, Simone Rizzetto, Auda Elthala, Elizabeth Keoshkerian, Jean-Louis Palgen, Timothy Peters, Thi H O Nguyen, Raymond Louie, Katherine Kedzierska, Silvana Gaudieri, Rowena A Bull, Andrew R Lloyd, Fabio Luciani.
      T cell exhaustion is a hallmark of hepatitis C virus (HCV) infection and limits protective immunity in chronic viral infections and cancer. Limited knowledge exists of the initial viral and immune dynamics that characterise exhaustion in humans. We studied longitudinal blood samples from a unique cohort of individuals with primary infection using single-cell multi-omics to identify the functions and phenotypes of HCV-specific CD8+ T cells. Early elevated IFN-γ response against the transmitted virus is associated with the rate of immune escape, larger clonal expansion, and early onset of exhaustion. Irrespective of disease outcome, we find heterogeneous subsets of progenitors of exhaustion, based on the level of PD-1 expression and loss of AP-1 transcription factors. Intra-clonal analysis shows distinct trajectories with multiple fates and evolutionary plasticity of precursor cells. These findings challenge the current paradigm on the contribution of CD8+ T cells to HCV disease outcome and provide data for future studies on T cell differentiation in human infections.
    DOI:  https://doi.org/10.1038/s41467-022-35281-7
  29. Commun Biol. 2022 Dec 05. 5(1): 1332
    KLF4-PFKFB3-driven glycolysis is essential for phenotypic switching of vascular smooth muscle cells.
    Xinhua Zhang, Bin Zheng, Lingdan Zhao, Jiayi Shen, Zhan Yang, Yu Zhang, Ruirui Fan, Manli Zhang, Dong Ma, Lemin Zheng, Mingming Zhao, Huirong Liu, Jinkun Wen.
      Vascular smooth muscle cells (VSMCs) within atherosclerotic lesions undergo a phenotypic switching in a KLF4-dependent manner. Glycolysis plays important roles in transdifferentiation of somatic cells, however, it is unclear whether and how KLF4 mediates the link between glycolytic switch and VSMCs phenotypic transitions. Here, we show that KLF4 upregulation accompanies VSMCs phenotypic switching in atherosclerotic lesions. KLF4 enhances the metabolic switch to glycolysis through increasing PFKFB3 expression. Inhibiting glycolysis suppresses KLF4-induced VSMCs phenotypic switching, demonstrating that glycolytic shift is required for VSMCs phenotypic switching. Mechanistically, KLF4 upregulates expression of circCTDP1 and eEF1A2, both of which cooperatively promote PFKFB3 expression. TMAO induces glycolytic shift and VSMCs phenotypic switching by upregulating KLF4. Our study indicates that KLF4 mediates the link between glycolytic switch and VSMCs phenotypic transitions, suggesting that a previously unrecognized KLF4-eEF1A2/circCTDP1-PFKFB3 axis plays crucial roles in VSMCs phenotypic switching.
    DOI:  https://doi.org/10.1038/s42003-022-04302-y
  30. Immunity. 2022 Nov 17. pii: S1074-7613(22)00597-0. [Epub ahead of print]
    Functional proteomic profiling links deficient DNA clearance with increased mortality in individuals with severe COVID-19 pneumonia.
    Iker Valle Aramburu, Dennis Hoving, Spyros I Vernardis, Martha C F Tin, Marianna Ioannou, Mia I Temkin, Nathalia M De Vasconcelos, Vadim Demichev, Elisa Theresa Helbig, Lena Lippert, Klaus Stahl, Matthew White, Helena Radbruch, Jana Ihlow, David Horst, Scott T Chiesa, John E Deanfield, Sascha David, Christian Bode, Florian Kurth, Markus Ralser, Venizelos Papayannopoulos.
      The factors that influence survival during severe infection are unclear. Extracellular chromatin drives pathology, but the mechanisms enabling its accumulation remain elusive. Here, we show that in murine sepsis models, splenocyte death interferes with chromatin clearance through the release of the DNase I inhibitor actin. Actin-mediated inhibition was compensated by upregulation of DNase I or the actin scavenger gelsolin. Splenocyte death and neutrophil extracellular trap (NET) clearance deficiencies were prevalent in individuals with severe COVID-19 pneumonia or microbial sepsis. Activity tracing by plasma proteomic profiling uncovered an association between low NET clearance and increased COVID-19 pathology and mortality. Low NET clearance activity with comparable proteome associations was prevalent in healthy donors with low-grade inflammation, implicating defective chromatin clearance in the development of cardiovascular disease and linking COVID-19 susceptibility to pre-existing conditions. Hence, the combination of aberrant chromatin release with defects in protective clearance mechanisms lead to poor survival outcomes.
    Keywords:  COVID-19; DNA; DNase I; NETs; actin; degradation; histone; inflammation; proteomics; sepsis
    DOI:  https://doi.org/10.1016/j.immuni.2022.11.007
  31. Nat Commun. 2022 Dec 08. 13(1): 7582
    Differential IL18 signaling via IL18 receptor and Na-Cl co-transporter discriminating thermogenesis and glucose metabolism regulation.
    Xian Zhang, Songyuan Luo, Minjie Wang, Qiongqiong Cao, Zhixin Zhang, Qin Huang, Jie Li, Zhiyong Deng, Tianxiao Liu, Cong-Lin Liu, Mathilde Meppen, Amelie Vromman, Richard A Flavell, Gökhan S Hotamışlıgil, Jian Liu, Peter Libby, Zhangsuo Liu, Guo-Ping Shi.
      White adipose tissue (WAT) plays a role in storing energy, while brown adipose tissue (BAT) is instrumental in the re-distribution of stored energy when dietary sources are unavailable. Interleukin-18 (IL18) is a cytokine playing a role in T-cell polarization, but also for regulating energy homeostasis via the dimeric IL18 receptor (IL18r) and Na-Cl co-transporter (NCC) on adipocytes. Here we show that IL18 signaling in metabolism is regulated at the level of receptor utilization, with preferential role for NCC in brown adipose tissue (BAT) and dominantly via IL18r in WAT. In Il18r-/-Ncc-/- mice, high-fat diet (HFD) causes more prominent body weight gain and insulin resistance than in wild-type mice. The WAT insulin resistance phenotype of the double-knockout mice is recapitulated in HFD-fed Il18r-/- mice, whereas decreased thermogenesis in BAT upon HFD is dependent on NCC deletion. BAT-selective depletion of either NCC or IL18 reduces thermogenesis and increases BAT and WAT inflammation. IL18r deletion in WAT reduces insulin signaling and increases WAT inflammation. In summary, our study contributes to the mechanistic understanding of IL18 regulation of energy metabolism and shows clearly discernible roles for its two receptors in brown and white adipose tissues.
    DOI:  https://doi.org/10.1038/s41467-022-35256-8
  32. Nat Commun. 2022 Dec 09. 13(1): 7627
    High-throughput robust single-cell DNA methylation profiling with sciMETv2.
    Ruth V Nichols, Brendan L O'Connell, Ryan M Mulqueen, Jerushah Thomas, Ashley R Woodfin, Sonia Acharya, Gail Mandel, Dmitry Pokholok, Frank J Steemers, Andrew C Adey.
      DNA methylation is a key epigenetic property that drives gene regulatory programs in development and disease. Current single-cell methods that produce high quality methylomes are expensive and low throughput without the aid of extensive automation. We previously described a proof-of-principle technique that enabled high cell throughput; however, it produced only low-coverage profiles and was a difficult protocol that required custom sequencing primers and recipes and frequently produced libraries with excessive adapter contamination. Here, we describe a greatly improved version that generates high-coverage profiles (~15-fold increase) using a robust protocol that does not require custom sequencing capabilities, includes multiple stopping points, and exhibits minimal adapter contamination. We demonstrate two versions of sciMETv2 on primary human cortex, a high coverage and rapid version, identifying distinct cell types using CH methylation patterns. These datasets are able to be directly integrated with one another as well as with existing snmC-seq2 datasets with little discernible bias. Finally, we demonstrate the ability to determine cell types using CG methylation alone, which is the dominant context for DNA methylation in most cell types other than neurons and the most applicable analysis outside of brain tissue.
    DOI:  https://doi.org/10.1038/s41467-022-35374-3
  33. Nat Commun. 2022 Dec 03. 13(1): 7467
    Membrane curvature governs the distribution of Piezo1 in live cells.
    Shilong Yang, Xinwen Miao, Steven Arnold, Boxuan Li, Alan T Ly, Huan Wang, Matthew Wang, Xiangfu Guo, Medha M Pathak, Wenting Zhao, Charles D Cox, Zheng Shi.
      Piezo1 is a bona fide mechanosensitive ion channel ubiquitously expressed in mammalian cells. The distribution of Piezo1 within a cell is essential for various biological processes including cytokinesis, cell migration, and wound healing. However, the underlying principles that guide the subcellular distribution of Piezo1 remain largely unexplored. Here, we demonstrate that membrane curvature serves as a key regulator of the spatial distribution of Piezo1 in the plasma membrane of living cells. Piezo1 depletes from highly curved membrane protrusions such as filopodia and enriches to nanoscale membrane invaginations. Quantification of the curvature-dependent sorting of Piezo1 directly reveals the in situ nano-geometry of the Piezo1-membrane complex. Piezo1 density on filopodia increases upon activation, independent of calcium, suggesting flattening of the channel upon opening. Consequently, the expression of Piezo1 inhibits filopodia formation, an effect that diminishes with channel activation.
    DOI:  https://doi.org/10.1038/s41467-022-35034-6
  34. Nat Commun. 2022 Dec 08. 13(1): 7583
    Divergent self-association properties of paralogous proteins TRIM2 and TRIM3 regulate their E3 ligase activity.
    Diego Esposito, Jane Dudley-Fraser, Acely Garza-Garcia, Katrin Rittinger.
      Tripartite motif (TRIM) proteins constitute a large family of RING-type E3 ligases that share a conserved domain architecture. TRIM2 and TRIM3 are paralogous class VII TRIM members that are expressed mainly in the brain and regulate different neuronal functions. Here we present a detailed structure-function analysis of TRIM2 and TRIM3, which despite high sequence identity, exhibit markedly different self-association and activity profiles. We show that the isolated RING domain of human TRIM3 is monomeric and inactive, and that this lack of activity is due to a few placental mammal-specific amino acid changes adjacent to the core RING domain that prevent self-association but not E2 recognition. We demonstrate that the activity of human TRIM3 RING can be restored by substitution with the relevant region of human TRIM2 or by hetero-dimerization with human TRIM2, establishing that subtle amino acid changes can profoundly affect TRIM protein activity. Finally, we show that TRIM2 and TRIM3 interact in a cellular context via their filamin and coiled-coil domains, respectively.
    DOI:  https://doi.org/10.1038/s41467-022-35300-7
  35. Commun Biol. 2022 Dec 06. 5(1): 1335
    The deubiquitinating enzyme complex BRISC regulates Aurora B activation via lysine-63-linked ubiquitination in mitosis.
    Qin Li, Yanfang Ma, Fen Chang, Yongjie Xu, Jingcheng Deng, Junyi Duan, Wei Jiang, Qihua He, Luzheng Xu, Lijun Zhong, Genze Shao, Li Li.
      Faithful chromosome segregation requires bi-oriented kinetochore-microtubule attachment on the metaphase spindle. Aurora B kinase, the catalytic core of the chromosome passage complex (CPC), plays a crucial role in this process. Aurora B activation has widely been investigated in the context of protein phosphorylation. Here, we report that Aurora B is ubiquitinated in mitosis through lysine-63 ubiquitin chains (K63-Ub), which is required for its activation. Mutation of Aurora B at its primary K63 ubiquitin site inhibits its activation, reduces its kinase activity, and disrupts the association of Aurora B with other components of CPC, leading to severe mitotic defects and cell apoptosis. Moreover, we identify that BRCC36 isopeptidase complex (BRISC) is the K63-specific deubiquitinating enzyme for Aurora B. BRISC deficiency augments the accumulation of Aurora B K63-Ubs, leading to Aurora B hyperactivation and erroneous chromosome-microtubule attachments. These findings define the role of K63-linked ubiquitination in regulating Aurora B activation and provide a potential site for Aurora B-targeting drug design.
    DOI:  https://doi.org/10.1038/s42003-022-04299-4
  36. Nat Commun. 2022 Dec 03. 13(1): 7478
    Cryo-EM structure of ssDNA bacteriophage ΦCjT23 provides insight into early virus evolution.
    Nejc Kejzar, Elina Laanto, Ilona Rissanen, Vahid Abrishami, Muniyandi Selvaraj, Sylvain Moineau, Janne Ravantti, Lotta-Riina Sundberg, Juha T Huiskonen.
      The origin of viruses remains an open question. While lack of detectable sequence similarity hampers the analysis of distantly related viruses, structural biology investigations of conserved capsid protein structures facilitate the study of distant evolutionary relationships. Here we characterize the lipid-containing ssDNA temperate bacteriophage ΦCjT23, which infects Flavobacterium sp. (Bacteroidetes). We report ΦCjT23-like sequences in the genome of strains belonging to several Flavobacterium species. The virion structure determined by cryogenic electron microscopy reveals similarities to members of the viral kingdom Bamfordvirae that currently consists solely of dsDNA viruses with a major capsid protein composed of two upright β-sandwiches. The minimalistic structure of ΦCjT23 suggests that this phage serves as a model for the last common ancestor between ssDNA and dsDNA viruses in the Bamfordvirae. Both ΦCjT23 and the related phage FLiP infect Flavobacterium species found in several environments, suggesting that these types of viruses have a global distribution and a shared evolutionary origin. Detailed comparisons to related, more complex viruses not only expand our knowledge about this group of viruses but also provide a rare glimpse into early virus evolution.
    DOI:  https://doi.org/10.1038/s41467-022-35123-6
  37. Dev Cell. 2022 Dec 06. pii: S1534-5807(22)00812-7. [Epub ahead of print]
    Langerhans cells are essential components of the angiogenic niche during murine skin repair.
    Renee Wasko, Kate Bridges, Rebecca Pannone, Ikjot Sidhu, Yue Xing, Shruti Naik, Kathryn Miller-Jensen, Valerie Horsley.
      Angiogenesis, the growth of new blood vessels from pre-existing vessels, occurs during development, injury repair, and tumorigenesis to deliver oxygen, immune cells, and nutrients to tissues. Defects in angiogenesis occur in cardiovascular and inflammatory diseases, and chronic, non-healing wounds, yet treatment options are limited. Here, we provide a map of the early angiogenic niche by analyzing single-cell RNA sequencing of mouse skin wound healing. Our data implicate Langerhans cells (LCs), phagocytic, skin-resident immune cells, in driving angiogenesis during skin repair. Using lineage-driven reportersw, three-dimensional (3D) microscopy, and mouse genetics, we show that LCs are situated at the endothelial cell leading edge in mouse skin wounds and are necessary for angiogenesis during repair. These data provide additional future avenues for the control of angiogenesis to treat disease and chronic wounds and extend the function of LCs beyond their canonical role in antigen presentation and T cell immunity.
    Keywords:  Endothelial cells; Langerhans cells; angiogenesis; single-cell RNA sequencing; skin; tissue repair; wound healing
    DOI:  https://doi.org/10.1016/j.devcel.2022.11.012
  38. Nat Commun. 2022 Dec 03. 13(1): 7208
    Community voices: broadening participation in Science, Technology, Engineering, Mathematics, and Medicine among persons with disabilities.
    Siobhán M Mattison, Logan Gin, Allistair A Abraham, Megan Moodie, Feranmi Okanlami, Katherine Wander.
      
    DOI:  https://doi.org/10.1038/s41467-022-34711-w
  39. Nat Commun. 2022 Dec 07. 13(1): 7554
    An in silico method to assess antibody fragment polyreactivity.
    Edward P Harvey, Jung-Eun Shin, Meredith A Skiba, Genevieve R Nemeth, Joseph D Hurley, Alon Wellner, Ada Y Shaw, Victor G Miranda, Joseph K Min, Chang C Liu, Debora S Marks, Andrew C Kruse.
      Antibodies are essential biological research tools and important therapeutic agents, but some exhibit non-specific binding to off-target proteins and other biomolecules. Such polyreactive antibodies compromise screening pipelines, lead to incorrect and irreproducible experimental results, and are generally intractable for clinical development. Here, we design a set of experiments using a diverse naïve synthetic camelid antibody fragment (nanobody) library to enable machine learning models to accurately assess polyreactivity from protein sequence (AUC > 0.8). Moreover, our models provide quantitative scoring metrics that predict the effect of amino acid substitutions on polyreactivity. We experimentally test our models' performance on three independent nanobody scaffolds, where over 90% of predicted substitutions successfully reduced polyreactivity. Importantly, the models allow us to diminish the polyreactivity of an angiotensin II type I receptor antagonist nanobody, without compromising its functional properties. We provide a companion web-server that offers a straightforward means of predicting polyreactivity and polyreactivity-reducing mutations for any given nanobody sequence.
    DOI:  https://doi.org/10.1038/s41467-022-35276-4
  40. Nat Commun. 2022 Dec 03. 13(1): 7477
    Genetic features and therapeutic relevance of emergent circulating tumor DNA alterations in refractory non-colorectal gastrointestinal cancers.
    David Hsiehchen, Leslie Bucheit, Dong Yang, Muhammad Shaalan Beg, Mir Lim, Sunyoung S Lee, Pashtoon Murtaza Kasi, Ahmed O Kaseb, Hao Zhu.
      Acquired resistance to systemic treatments is inevitable in most cancers, but the genetic basis for this in many cancer types has remained elusive due to constraints in obtaining tissue specimens longitudinally. In the management of gastrointestinal cancers, molecular profiling is conventionally performed at a single time point, although serial evaluations may yield biological insights that inform treatment decisions. We characterize genetic changes in serial liquid biopsies which provide real-time snapshots of tumor genetics and heterogeneity in refractory non-colorectal gastrointestinal cancers, and determine the clinical utility of repeat circulating tumor DNA (ctDNA) testing. In a national cohort of 449 patients with pancreatic, biliary, esophagogastric, and hepatocellular cancers, resistance to conventional therapies is broadly associated with tumor evolution. Emergent ctDNA alterations only detectable at progression occurs in 63% of patients and are frequently associated with treatment actionability. Tumor mutation burden is dynamic in cancers undergoing treatment, but is not associated with time to progression. Objective tumor responses in a case series of patients receiving treatment matched to emergent alterations show that repeat liquid biopsies may have clinical benefit by expanding treatment options in advanced gastrointestinal cancers.
    DOI:  https://doi.org/10.1038/s41467-022-35144-1
  41. Nat Commun. 2022 Dec 06. 13(1): 7525
    Next generation genetically encoded fluorescent sensors for serotonin.
    Martin Kubitschke, Monika Müller, Lutz Wallhorn, Mauro Pulin, Manuel Mittag, Stefan Pollok, Tim Ziebarth, Svenja Bremshey, Jill Gerdey, Kristin Carolin Claussen, Kim Renken, Juliana Groß, Pascal Gneiße, Niklas Meyer, J Simon Wiegert, Andreas Reiner, Martin Fuhrmann, Olivia Andrea Masseck.
      We developed a family of genetically encoded serotonin (5-HT) sensors (sDarken) on the basis of the native 5-HT1A receptor and circularly permuted GFP. sDarken 5-HT sensors are bright in the unbound state and diminish their fluorescence upon binding of 5-HT. Sensor variants with different affinities for serotonin were engineered to increase the versatility in imaging of serotonin dynamics. Experiments in vitro and in vivo showed the feasibility of imaging serotonin dynamics with high temporal and spatial resolution. As demonstrated here, the designed sensors show excellent membrane expression, have high specificity and a superior signal-to-noise ratio, detect the endogenous release of serotonin and are suitable for two-photon in vivo imaging.
    DOI:  https://doi.org/10.1038/s41467-022-35200-w
  42. Nature. 2022 Dec 08.
    Principles of mitoribosomal small subunit assembly in eukaryotes.
    Nathan J Harper, Chloe Burnside, Sebastian Klinge.
      Mitochondrial ribosomes (mitoribosomes) synthesize proteins encoded within the mitochondrial genome that are assembled into oxidative phosphorylation complexes. Thus, mitoribosome biogenesis is essential for ATP production and cellular metabolism1. Here we used cryo-electron microscopy to determine 9 structures of native yeast and human mitoribosomal small subunit assembly intermediates at resolutions from 2.4 to 3.8 Å, illuminating the mechanistic basis for how GTPases are employed to control early steps of decoding center formation, how initial rRNA folding and processing events are mediated, and how mitoribosomal proteins play active roles during assembly. Furthermore, this series of intermediates from two species with divergent mitoribosomal architecture uncovers both conserved principles and species-specific adaptations that govern the maturation of mitoribosomal small subunits in eukaryotes. By revealing the dynamic interplay between assembly factors, mitoribosomal proteins, and rRNA required to generate functional subunits, our structural analysis provides a vignette for how molecular complexity and diversity can evolve in large ribonucleoprotein assemblies.
    DOI:  https://doi.org/10.1038/s41586-022-05621-0
  43. Nature. 2022 Dec 09.
    Why is strep A surging - and how worried are scientists?
    Heidi Ledford.
      
    Keywords:  Diseases; Infection; Public health
    DOI:  https://doi.org/10.1038/d41586-022-04403-y
  44. Nat Genet. 2022 Dec;54(12): 1895-1906
    Evidence that direct inhibition of transcription factor binding is the prevailing mode of gene and repeat repression by DNA methylation.
    Sebastian Kaluscha, Silvia Domcke, Christiane Wirbelauer, Michael B Stadler, Sevi Durdu, Lukas Burger, Dirk Schübeler.
      Cytosine methylation efficiently silences CpG-rich regulatory regions of genes and repeats in mammalian genomes. To what extent this entails direct inhibition of transcription factor (TF) binding versus indirect inhibition via recruitment of methyl-CpG-binding domain (MBD) proteins is unclear. Here we show that combinatorial genetic deletions of all four proteins with functional MBDs in mouse embryonic stem cells, derived neurons or a human cell line do not reactivate genes or repeats with methylated promoters. These do, however, become activated by methylation-restricted TFs if DNA methylation is removed. We identify several causal TFs in neurons, including ONECUT1, which is methylation sensitive only at a motif variant. Rampantly upregulated retrotransposons in methylation-free neurons feature a CRE motif, which activates them in the absence of DNA methylation via methylation-sensitive binding of CREB1. Our study reveals methylation-sensitive TFs in vivo and argues that direct inhibition, rather than indirect repression by the tested MBD proteins, is the prevailing mechanism of methylation-mediated repression at regulatory regions and repeats.
    DOI:  https://doi.org/10.1038/s41588-022-01241-6
  45. Nature. 2022 Dec;612(7939): 209-210
    How smallpox inoculation united America.
    Heidi Ledford.
      
    Keywords:  History; Microbiology; Politics; Public health
    DOI:  https://doi.org/10.1038/d41586-022-04334-8
  46. Nat Commun. 2022 Dec 03. 13(1): 7479
    Dual communities in spatial networks.
    Franz Kaiser, Philipp C Böttcher, Henrik Ronellenfitsch, Vito Latora, Dirk Witthaut.
      Both human-made and natural supply systems, such as power grids and leaf venation networks, are built to operate reliably under changing external conditions. Many of these spatial networks exhibit community structures. Here, we show that a relatively strong connectivity between the parts of a network can be used to define a different class of communities: dual communities. We demonstrate that traditional and dual communities emerge naturally as two different phases of optimized network structures that are shaped by fluctuations and that they both suppress failure spreading, which underlines their importance in understanding the shape of real-world supply networks.
    DOI:  https://doi.org/10.1038/s41467-022-34939-6
  47. Cell Death Dis. 2022 Dec 09. 13(12): 1031
    Mechanistic target of rapamycin complex 1 orchestrates the interplay between hepatocytes and Kupffer cells to determine the outcome of immune-mediated hepatitis.
    Xiaoli Sun, Yajie Ni, Qingmiao Lu, Yan Liang, Mengru Gu, Xian Xue, Chunsun Dai.
      The cell-cell interaction between hepatocytes and Kupffer cells (KCs) is crucial for maintaining liver homeostasis, and the loss of KCs and hepatocytes is known to represent a common pathogenic phenomenon in autoimmune hepatitis. Until now, the mechanisms of cell-cell interaction between hepatocytes and KCs involved in immune-mediated hepatitis remains unclear. Here we dissected the impact of activated mTORC1 on the cell-cell interaction of KCs and hepatocyte in immune-mediated hepatitis. In the liver from patients with AIH and mice administrated with Con-A, mTORC1 was activated in both KCs and hepatocytes. The activated mTORC1 signal in hepatocytes with Con-A challenge caused a markedly production of miR-329-3p. Upregulated miR-329-3p inhibited SGMS1 expression in KCs through paracrine, resulting in the death of KCs. Most of maintained KCs were p-S6 positive and distributed in hepatocyte mTORC1 negative area. The activation of mTORC1 enabled KCs expressed complement factor B (CFB) to enhance the complement alternative system, which produced more complement factors to aggravate liver injury. Our findings remonstrate a heterogeneous role of mTORC1 in specific cell type for maintaining tolerogenic liver environment, and will form the basis for the development of new interventions against immune-mediated hepatitis.
    DOI:  https://doi.org/10.1038/s41419-022-05487-0
  48. Nat Commun. 2022 Dec 06. 13(1): 7430
    A metabolic associated fatty liver disease risk variant in MBOAT7 regulates toll like receptor induced outcomes.
    Jawaher Alharthi, Ali Bayoumi, Khaled Thabet, Ziyan Pan, Brian S Gloss, Olivier Latchoumanin, Mischa Lundberg, Natalie A Twine, Duncan McLeod, Shafi Alenizi, Leon A Adams, Martin Weltman, Thomas Berg, Christopher Liddle, Jacob George, Mohammed Eslam.
      The breakdown of toll-like receptor (TLR) tolerance results in tissue damage, and hyperactivation of the TLRs and subsequent inflammatory consequences have been implicated as risk factors for more severe forms of disease and poor outcomes from various diseases including COVID-19 and metabolic (dysfunction) associated fatty liver disease (MAFLD). Here we provide evidence that membrane bound O-acyltransferase domain containing 7 (MBOAT7) is a negative regulator of TLR signalling. MBOAT7 deficiency in macrophages as observed in patients with MAFLD and in COVID-19, alters membrane phospholipid composition. We demonstrate that this is associated with a redistribution of arachidonic acid toward proinflammatory eicosanoids, induction of endoplasmic reticulum stress, mitochondrial dysfunction, and remodelling of the accessible inflammatory-related chromatin landscape culminating in macrophage inflammatory responses to TLRs. Activation of MBOAT7 reverses these effects. These outcomes are further modulated by the MBOAT7 rs8736 (T) MAFLD risk variant. Our findings suggest that MBOAT7 can potentially be explored as a therapeutic target for diseases associated with dysregulation of the TLR signalling cascade.
    DOI:  https://doi.org/10.1038/s41467-022-35158-9
  49. Nat Commun. 2022 Dec 09. 13(1): 7613
    Meteorin-like is an injectable peptide that can enhance regeneration in aged muscle through immune-driven fibro/adipogenic progenitor signaling.
    David E Lee, Lauren K McKay, Akshay Bareja, Yongwu Li, Alastair Khodabukus, Nenad Bursac, Gregory A Taylor, Gurpreet S Baht, James P White.
      Pathologies associated with sarcopenia include decline in muscular strength, lean mass and regenerative capacity. Despite the substantial impact on quality of life, no pharmacological therapeutics are available to counteract the age-associated decline in functional capacity and/or, resilience. Evidence suggests immune-secreted cytokines can improve muscle regeneration, a strategy which we leverage in this study by rescuing the age-related deficiency in Meteorin-like through several in vivo add-back models. Notably, the intramuscular, peptide injection of recombinant METRNL was sufficient to improve muscle regeneration in aging. Using ex vivo media exchange and in vivo TNF inhibition, we demonstrate a mechanism of METRNL action during regeneration, showing it counteracts a pro-fibrotic gene program by triggering TNFα-induced apoptosis of fibro/adipogenic progenitor cells. These findings demonstrate therapeutic applications for METRNL to improve aged muscle, and show Fibro/Adipogenic Progenitors are viable therapeutic targets to counteract age-related loss in muscle resilience.
    DOI:  https://doi.org/10.1038/s41467-022-35390-3
  50. Nat Commun. 2022 Dec 03. 13(1): 7470
    Retrotransposon instability dominates the acquired mutation landscape of mouse induced pluripotent stem cells.
    Patricia Gerdes, Sue Mei Lim, Adam D Ewing, Michael R Larcombe, Dorothy Chan, Francisco J Sanchez-Luque, Lucinda Walker, Alexander L Carleton, Cini James, Anja S Knaupp, Patricia E Carreira, Christian M Nefzger, Ryan Lister, Sandra R Richardson, Jose M Polo, Geoffrey J Faulkner.
      Induced pluripotent stem cells (iPSCs) can in principle differentiate into any cell of the body, and have revolutionized biomedical research and regenerative medicine. Unlike their human counterparts, mouse iPSCs (miPSCs) are reported to silence transposable elements and prevent transposable element-mediated mutagenesis. Here we apply short-read or Oxford Nanopore Technologies long-read genome sequencing to 38 bulk miPSC lines reprogrammed from 10 parental cell types, and 18 single-cell miPSC clones. While single nucleotide variants and structural variants restricted to miPSCs are rare, we find 83 de novo transposable element insertions, including examples intronic to Brca1 and Dmd. LINE-1 retrotransposons are profoundly hypomethylated in miPSCs, beyond other transposable elements and the genome overall, and harbor alternative protein-coding gene promoters. We show that treatment with the LINE-1 inhibitor lamivudine does not hinder reprogramming and efficiently blocks endogenous retrotransposition, as detected by long-read genome sequencing. These experiments reveal the complete spectrum and potential significance of mutations acquired by miPSCs.
    DOI:  https://doi.org/10.1038/s41467-022-35180-x
  51. Nat Commun. 2022 Dec 09. 13(1): 7623
    Noradrenergic signaling mediates cortical early tagging and storage of remote memory.
    Xiaocen Fan, Jiachen Song, Chaonan Ma, Yanbo Lv, Feifei Wang, Lan Ma, Xing Liu.
      The neocortical prefrontal memory engram generated during initial learning is critical for remote episodic memory storage, however, the nature of early cortical tagging remains unknown. Here we found that in mice, increased norepinephrine (NE) release from the locus coeruleus (LC) to the medial prefrontal cortex (mPFC) during contextual fear conditioning (CFC) was critical for engram tagging and remote memory storage, which was regulated by the ventrolateral periaqueductal grey. β-Blocker infusion, or knockout of β1-adrenergic receptor (β1-AR) in the mPFC, impaired the storage of remote CFC memory, which could not be rescued by activation of LC-mPFC NE projection. Remote memory retrieval induced the activation of mPFC engram cells that were tagged during CFC. Inhibition of LC-mPFC NE projection or β1-AR knockout impaired mPFC engram tagging. Juvenile mice had fewer LC NE neurons than adults and showed deficiency in mPFC engram tagging and remote memory of CFC. Activation of β1-AR signaling promoted mPFC early tagging and remote memory storage in juvenile mice. Our data demonstrate that activation of LC NEergic signaling during CFC memory encoding mediates engram early tagging in the mPFC and systems consolidation of remote memory.
    DOI:  https://doi.org/10.1038/s41467-022-35342-x
  52. Nat Cell Biol. 2022 Dec;24(12): 1701-1713
    LDL delivery of microbial small RNAs drives atherosclerosis through macrophage TLR8.
    Ryan M Allen, Danielle L Michell, Ashley B Cavnar, Wanying Zhu, Neil Makhijani, Danielle M Contreras, Chase A Raby, Elizabeth M Semler, Carlisle DeJulius, Mark Castleberry, Youmin Zhang, Marisol Ramirez-Solano, Shilin Zhao, Craig Duvall, Amanda C Doran, Quanhu Sheng, MacRae F Linton, Kasey C Vickers.
      Macrophages present a spectrum of phenotypes that mediate both the pathogenesis and resolution of atherosclerotic lesions. Inflammatory macrophage phenotypes are pro-atherogenic, but the stimulatory factors that promote these phenotypes remain incompletely defined. Here we demonstrate that microbial small RNAs (msRNA) are enriched on low-density lipoprotein (LDL) and drive pro-inflammatory macrophage polarization and cytokine secretion via activation of the RNA sensor toll-like receptor 8 (TLR8). Removal of msRNA cargo during LDL re-constitution yields particles that readily promote sterol loading but fail to stimulate inflammatory activation. Competitive antagonism of TLR8 with non-targeting locked nucleic acids was found to prevent native LDL-induced macrophage polarization in vitro, and re-organize lesion macrophage phenotypes in vivo, as determined by single-cell RNA sequencing. Critically, this was associated with reduced disease burden in distinct mouse models of atherosclerosis. These results identify LDL-msRNA as instigators of atherosclerosis-associated inflammation and support alternative functions of LDL beyond cholesterol transport.
    DOI:  https://doi.org/10.1038/s41556-022-01030-7
  53. Nat Commun. 2022 Dec 09. 13(1): 7601
    Visualizing the transiently populated closed-state of human HSP90 ATP binding domain.
    Faustine Henot, Elisa Rioual, Adrien Favier, Pavel Macek, Elodie Crublet, Pierre Josso, Bernhard Brutscher, Matthias Frech, Pierre Gans, Claire Loison, Jerome Boisbouvier.
      HSP90 are abundant molecular chaperones, assisting the folding of several hundred client proteins, including substrates involved in tumor growth or neurodegenerative diseases. A complex set of large ATP-driven structural changes occurs during HSP90 functional cycle. However, the existence of such structural rearrangements in apo HSP90 has remained unclear. Here, we identify a metastable excited state in the isolated human HSP90α ATP binding domain. We use solution NMR and mutagenesis to characterize structures of both ground and excited states. We demonstrate that in solution the HSP90α ATP binding domain transiently samples a functionally relevant ATP-lid closed state, distant by more than 30 Å from the ground state. NMR relaxation enables to derive information on the kinetics and thermodynamics of this interconversion, while molecular dynamics simulations establish that the ATP-lid in closed conformation is a metastable exited state. The precise description of the dynamics and structures sampled by human HSP90α ATP binding domain provides information for the future design of new therapeutic ligands.
    DOI:  https://doi.org/10.1038/s41467-022-35399-8
  54. Nat Commun. 2022 Dec 06. 13(1): 7512
    Multiple drivers and lineage-specific insect extinctions during the Permo-Triassic.
    Corentin Jouault, André Nel, Vincent Perrichot, Frédéric Legendre, Fabien L Condamine.
      The Permo-Triassic interval encompasses three extinction events including the most dramatic biological crisis of the Phanerozoic, the latest Permian mass extinction. However, their drivers and outcomes are poorly quantified and understood for terrestrial invertebrates, which we assess here for insects. We find a pattern with three extinctions: the Roadian/Wordian (≈266.9 Ma; extinction of 64.5% insect genera), the Permian/Triassic (≈252 Ma; extinction of 82.6% insect genera), and the Ladinian/Carnian boundaries (≈237 Ma; extinction of 74.8% insect genera). We also unveil a heterogeneous effect of these extinction events across the major insect clades. Because extinction events have impacted Permo-Triassic ecosystems, we investigate the influence of abiotic and biotic factors on insect diversification dynamics and find that changes in floral assemblages are likely the strongest drivers of insects' responses throughout the Permo-Triassic. We also assess the effect of diversity dependence between three insect guilds; an effect ubiquitously found in current ecosystems. We find that herbivores held a central position in the Permo-Triassic interaction network. Our study reveals high levels of insect extinction that profoundly shaped the evolutionary history of the most diverse non-microbial lineage.
    DOI:  https://doi.org/10.1038/s41467-022-35284-4
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