bims-nimamd Biomed News
on Neuroimmunity and neuroinflammation in ageing and metabolic disease
Issue of 2024–02–25
fifty papers selected by
Fawaz Alzaïd, Sorbonne Université
  1. Embracing my difference.
  2. Monocarboxylate transporters facilitate succinate uptake into brown adipocytes.
  3. A co-assembly platform engaging macrophage scavenger receptor A for lysosome-targeting protein degradation.
  4. The gene regulatory basis of bystander activation in CD8+ T cells.
  5. Stalled translation by mitochondrial stress upregulates a CNOT4-ZNF598 ribosomal quality control pathway important for tissue homeostasis.
  6. Intestinal IL-22RA1 signaling regulates intrinsic and systemic lipid and glucose metabolism to alleviate obesity-associated disorders.
  7. Genetic drivers of heterogeneity in type 2 diabetes pathophysiology.
  8. ALLO-1- and IKKE-1-dependent positive feedback mechanism promotes the initiation of paternal mitochondrial autophagy.
  9. Gonococcal OMV-delivered PorB induces epithelial cell mitophagy.
  10. Regulatory T cells use heparanase to access IL-2 bound to extracellular matrix in inflamed tissue.
  11. Metabolic regulation of chemoresistance and immuno-surveillance in AML by SHP-1.
  12. IL-10 constrains sphingolipid metabolism to limit inflammation.
  13. M2 macrophages independently promote beige adipogenesis via blocking adipocyte Ets1.
  14. Quantitative live cell imaging of a tauopathy model enables the identification of a polypharmacological drug candidate that restores physiological microtubule interaction.
  15. Learning representations for image-based profiling of perturbations.
  16. Judith Campisi (1948-2024), cell biologist who explored how cells age.
  17. A mechanism for BCG vaccine cross-protection against pulmonary viral infections.
  18. A transient protein folding response targets aggregation in the early phase of TDP-43-mediated neurodegeneration.
  19. Simultaneous targeting of POMC and AgRP neurons.
  20. scCASE: accurate and interpretable enhancement for single-cell chromatin accessibility sequencing data.
  21. DIAPH1-MFN2 interaction decreases the endoplasmic reticulum-mitochondrial distance and promotes cardiac injury following myocardial ischemia.
  22. The regulation and differentiation of regulatory T cells and their dysfunction in autoimmune diseases.
  23. Mapping T cell landscapes in B cell lymphomas.
  24. Runx1+ vascular smooth muscle cells are essential for hematopoietic stem and progenitor cell development in vivo.
  25. A single cell atlas of frozen shoulder capsule identifies features associated with inflammatory fibrosis resolution.
  26. Ambitious survey of human diversity yields millions of undiscovered genetic variants.
  27. Denaturing purifications demonstrate that PRC2 and other widely reported chromatin proteins do not appear to bind directly to RNA in vivo.
  28. Longitudinal analysis shows how microbiome changes might influence responses to immune checkpoint blockade.
  29. How we boosted female faculty numbers in male-dominated departments.
  30. IgG is an aging factor that drives adipose tissue fibrosis and metabolic decline.
  31. Exosomes define a local and systemic communication network in healthy pancreas and pancreatic ductal adenocarcinoma.
  32. A nasal vaccine elicits protective CD8+ T cell immunity against antigen shifted SARS-CoV-2 virus.
  33. Meiotic protein SYCP2 confers resistance to DNA-damaging agents through R-loop-mediated DNA repair.
  34. Designer high-density lipoprotein particles enhance endothelial barrier function and suppress inflammation.
  35. The UFM1 E3 ligase recognizes and releases 60S ribosomes from ER translocons.
  36. Functional plasticity of glutamatergic neurons of medullary reticular nuclei after spinal cord injury in mice.
  37. Targeted protein degradation via intramolecular bivalent glues.
  38. Transcription factor exchange enables prolonged transcriptional bursts.
  39. Spatiotemporal and direct capturing global substrates of lysine-modifying enzymes in living cells.
  40. Mechanistic insights from inflammasome structures.
  41. A mosquito salivary protein-driven influx of myeloid cells facilitates flavivirus transmission.
  42. Fasting-mimicking diet causes hepatic and blood markers changes indicating reduced biological age and disease risk.
  43. Integrating single-cell and spatially resolved transcriptomic strategies to survey the astrocyte response to stroke in male mice.
  44. Cellular senescence: Neither irreversible nor reversible.
  45. Bacteria employ lysine acetylation of transcriptional regulators to adapt gene expression to cellular metabolism.
  46. Drosophila TMEM63 and mouse TMEM63A are lysosomal mechanosensory ion channels.
  47. Global evaluation of lineage-specific human papillomavirus capsid antigenicity using antibodies elicited by natural infection.
  48. MCT1 helps brown fat suck up succinate.
  49. Leaky blood-brain barrier in long-COVID-associated brain fog.
  50. Chronic endoplasmic reticulum stress in myotonic dystrophy type 2 promotes autoimmunity via mitochondrial DNA release.
  1. Science. 2024 Feb 23. 383(6685): 926
    Embracing my difference.
    Charlotte Goeyers.
      
    DOI:  https://doi.org/10.1126/science.ado6861
  2. Nat Metab. 2024 Feb 20.
    Monocarboxylate transporters facilitate succinate uptake into brown adipocytes.
    Anita Reddy, Sally Winther, Nhien Tran, Haopeng Xiao, Josefine Jakob, Ryan Garrity, Arianne Smith, Martha Ordonez, Dina Laznik-Bogoslavski, Jeffrey D Rothstein, Evanna L Mills, Edward T Chouchani.
      Uptake of circulating succinate by brown adipose tissue (BAT) and beige fat elevates whole-body energy expenditure, counteracts obesity and antagonizes systemic tissue inflammation in mice. The plasma membrane transporters that facilitate succinate uptake in these adipocytes remain undefined. Here we elucidate a mechanism underlying succinate import into BAT via monocarboxylate transporters (MCTs). We show that succinate transport is strongly dependent on the proportion that is present in the monocarboxylate form. MCTs facilitate monocarboxylate succinate uptake, which is promoted by alkalinization of the cytosol driven by adrenoreceptor stimulation. In brown adipocytes, we show that MCT1 primarily facilitates succinate import. In male mice, we show that both acute pharmacological inhibition of MCT1 and congenital depletion of MCT1 decrease succinate uptake into BAT and consequent catabolism. In sum, we define a mechanism of succinate uptake in BAT that underlies its protective activity in mouse models of metabolic disease.
    DOI:  https://doi.org/10.1038/s42255-024-00981-5
  3. Nat Commun. 2024 Feb 23. 15(1): 1663
    A co-assembly platform engaging macrophage scavenger receptor A for lysosome-targeting protein degradation.
    Qian Wang, Xingyue Yang, Ruixin Yuan, Ao Shen, Pushu Wang, Haoting Li, Jun Zhang, Chao Tian, Zhujun Jiang, Wenzhe Li, Suwei Dong.
      Targeted degradation of proteins has emerged as a powerful method for modulating protein homeostasis. Identification of suitable degraders is essential for achieving effective protein degradation. Here, we present a non-covalent degrader construction strategy, based on a modular supramolecular co-assembly system consisting of two self-assembling peptide ligands that bind cell membrane receptors and the protein of interest simultaneously, resulting in targeted protein degradation. The developed lysosome-targeting co-assemblies (LYTACAs) can induce lysosomal degradation of extracellular protein IL-17A and membrane protein PD-L1 in several scavenger receptor A-expressing cell lines. The IL-17A-degrading co-assembly has been applied in an imiquimod-induced psoriasis mouse model, where it decreases IL-17A levels in the skin lesion and alleviates psoriasis-like inflammation. Extending to asialoglycoprotein receptor-related protein degradation, LYTACAs have demonstrated the versatility and potential in streamlining degraders for extracellular and membrane proteins.
    DOI:  https://doi.org/10.1038/s41467-024-46130-0
  4. Sci Immunol. 2024 Feb 23. 9(92): eadf8776
    The gene regulatory basis of bystander activation in CD8+ T cells.
    Neva B Watson, Ravi K Patel, Connor Kean, Janelle Veazey, Oyebola O Oyesola, Nathan Laniewski, Jennifer K Grenier, Jocelyn Wang, Cybelle Tabilas, Kristel J Yee Mon, Adrian J McNairn, Seth A Peng, Samantha P Wesnak, Kito Nzingha, Miles P Davenport, Elia D Tait Wojno, Kristin M Scheible, Norah L Smith, Andrew Grimson, Brian D Rudd.
      CD8+ T cells are classically recognized as adaptive lymphocytes based on their ability to recognize specific foreign antigens and mount memory responses. However, recent studies indicate that some antigen-inexperienced CD8+ T cells can respond to innate cytokines alone in the absence of cognate T cell receptor stimulation, a phenomenon referred to as bystander activation. Here, we demonstrate that neonatal CD8+ T cells undergo a robust and diverse program of bystander activation, which corresponds to enhanced innate-like protection against unrelated pathogens. Using a multi-omics approach, we found that the ability of neonatal CD8+ T cells to respond to innate cytokines derives from their capacity to undergo rapid chromatin remodeling, resulting in the usage of a distinct set of enhancers and transcription factors typically found in innate-like T cells. We observed that the switch between innate and adaptive functions in the CD8+ T cell compartment is mediated by changes in the abundance of distinct subsets of cells. The innate CD8+ T cell subset that predominates in early life was also present in adult mice and humans. Our findings provide support for the layered immune hypothesis and indicate that the CD8+ T cell compartment is more functionally diverse than previously thought.
    DOI:  https://doi.org/10.1126/sciimmunol.adf8776
  5. Nat Commun. 2024 Feb 22. 15(1): 1637
    Stalled translation by mitochondrial stress upregulates a CNOT4-ZNF598 ribosomal quality control pathway important for tissue homeostasis.
    Ji Geng, Shuangxi Li, Yu Li, Zhihao Wu, Sunil Bhurtel, Suman Rimal, Danish Khan, Rani Ohja, Onn Brandman, Bingwei Lu.
      Translational control exerts immediate effect on the composition, abundance, and integrity of the proteome. Ribosome-associated quality control (RQC) handles ribosomes stalled at the elongation and termination steps of translation, with ZNF598 in mammals and Hel2 in yeast serving as key sensors of translation stalling and coordinators of downstream resolution of collided ribosomes, termination of stalled translation, and removal of faulty translation products. The physiological regulation of RQC in general and ZNF598 in particular in multicellular settings is underexplored. Here we show that ZNF598 undergoes regulatory K63-linked ubiquitination in a CNOT4-dependent manner and is upregulated upon mitochondrial stresses in mammalian cells and Drosophila. ZNF598 promotes resolution of stalled ribosomes and protects against mitochondrial stress in a ubiquitination-dependent fashion. In Drosophila models of neurodegenerative diseases and patient cells, ZNF598 overexpression aborts stalled translation of mitochondrial outer membrane-associated mRNAs, removes faulty translation products causal of disease, and improves mitochondrial and tissue health. These results shed lights on the regulation of ZNF598 and its functional role in mitochondrial and tissue homeostasis.
    DOI:  https://doi.org/10.1038/s41467-024-45525-3
  6. Nat Commun. 2024 Feb 21. 15(1): 1597
    Intestinal IL-22RA1 signaling regulates intrinsic and systemic lipid and glucose metabolism to alleviate obesity-associated disorders.
    Stephen J Gaudino, Ankita Singh, Huakang Huang, Jyothi Padiadpu, Makheni Jean-Pierre, Cody Kempen, Tej Bahadur, Kiyoshi Shiomitsu, Richard Blumberg, Kenneth R Shroyer, Semir Beyaz, Natalia Shulzhenko, Andrey Morgun, Pawan Kumar.
      IL-22 is critical for ameliorating obesity-induced metabolic disorders. However, it is unknown where IL-22 acts to mediate these outcomes. Here we examine the importance of tissue-specific IL-22RA1 signaling in mediating long-term high fat diet (HFD) driven metabolic disorders. To do so, we generated intestinal epithelium-, liver-, and white adipose tissue (WAT)-specific Il22ra1 knockout and littermate control mice. Intestinal epithelium- and liver-specific IL-22RA1 signaling upregulated systemic glucose metabolism. Intestinal IL-22RA1 signaling also mediated liver and WAT metabolism in a microbiota-dependent manner. We identified an association between Oscillibacter and elevated WAT inflammation, likely induced by Mmp12 expressing macrophages. Mechanistically, transcription of intestinal lipid metabolism genes is regulated by IL-22 and potentially IL-22-induced IL-18. Lastly, we show that Paneth cell-specific IL-22RA1 signaling, in part, mediates systemic glucose metabolism after HFD. Overall, these results elucidate a key role of intestinal epithelium-specific IL-22RA1 signaling in regulating intestinal metabolism and alleviating systemic obesity-associated disorders.
    DOI:  https://doi.org/10.1038/s41467-024-45568-6
  7. Nature. 2024 Feb 19.
    Genetic drivers of heterogeneity in type 2 diabetes pathophysiology.
    VA Million Veteran Program
      Type 2 diabetes (T2D) is a heterogeneous disease that develops through diverse pathophysiological processes1,2 and molecular mechanisms that are often specific to cell type3,4. Here, to characterize the genetic contribution to these processes across ancestry groups, we aggregate genome-wide association study data from 2,535,601 individuals (39.7% not of European ancestry), including 428,452 cases of T2D. We identify 1,289 independent association signals at genome-wide significance (P < 5 × 10-8) that map to 611 loci, of which 145 loci are, to our knowledge, previously unreported. We define eight non-overlapping clusters of T2D signals that are characterized by distinct profiles of cardiometabolic trait associations. These clusters are differentially enriched for cell-type-specific regions of open chromatin, including pancreatic islets, adipocytes, endothelial cells and enteroendocrine cells. We build cluster-specific partitioned polygenic scores5 in a further 279,552 individuals of diverse ancestry, including 30,288 cases of T2D, and test their association with T2D-related vascular outcomes. Cluster-specific partitioned polygenic scores are associated with coronary artery disease, peripheral artery disease and end-stage diabetic nephropathy across ancestry groups, highlighting the importance of obesity-related processes in the development of vascular outcomes. Our findings show the value of integrating multi-ancestry genome-wide association study data with single-cell epigenomics to disentangle the aetiological heterogeneity that drives the development and progression of T2D. This might offer a route to optimize global access to genetically informed diabetes care.
    DOI:  https://doi.org/10.1038/s41586-024-07019-6
  8. Nat Commun. 2024 Feb 17. 15(1): 1460
    ALLO-1- and IKKE-1-dependent positive feedback mechanism promotes the initiation of paternal mitochondrial autophagy.
    Taeko Sasaki, Yasuharu Kushida, Takuya Norizuki, Hidetaka Kosako, Ken Sato, Miyuki Sato.
      Allophagy is responsible for the selective removal of paternally inherited organelles, including mitochondria, in Caenorhabditis elegans embryos, thereby facilitating the maternal inheritance of mitochondrial DNA. We previously identified two key factors in allophagy: an autophagy adaptor allophagy-1 (ALLO-1) and TBK1/IKKε family kinase IKKE-1. However, the precise mechanisms by which ALLO-1 and IKKE-1 regulate local autophagosome formation remain unclear. In this study, we identify two ALLO-1 isoforms with different substrate preferences during allophagy. Live imaging reveals a stepwise mechanism of ALLO-1 localization with rapid cargo recognition, followed by ALLO-1 accumulation around the cargo. In the ikke-1 mutant, the accumulation of ALLO-1, and not the recognition of cargo, is impaired, resulting in the failure of isolation membrane formation. Our results also suggest a feedback mechanism for ALLO-1 accumulation via EPG-7/ATG-11, a worm homolog of FIP200, which is a candidate for IKKE-1-dependent phosphorylation. This feedback mechanism may underlie the ALLO-1-dependent initiation and progression of autophagosome formation around paternal organelles.
    DOI:  https://doi.org/10.1038/s41467-024-45863-2
  9. Nat Commun. 2024 Feb 23. 15(1): 1669
    Gonococcal OMV-delivered PorB induces epithelial cell mitophagy.
    Shuai Gao, Lingyu Gao, Dailin Yuan, Xu'ai Lin, Stijn van der Veen.
      The bacterial pathogen Neisseria gonorrhoeae is able to invade epithelial cells and survive intracellularly. During this process, it secretes outer membrane vesicles (OMVs), however, the mechanistic details for interactions between gonococcal OMVs and epithelial cells and their impact on intracellular survival are currently not established. Here, we show that gonococcal OMVs induce epithelial cell mitophagy to reduce mitochondrial secretion of reactive oxygen species (ROS) and enhance intracellular survival. We demonstrate that OMVs deliver PorB to mitochondria to dissipate the mitochondrial membrane potential, resulting in mitophagy induction through a conventional PINK1 and OPTN/NDP52 mechanism. Furthermore, PorB directly recruits the E3 ubiquitin ligase RNF213, which decorates PorB lysine residue 171 with K63-linked polyubiquitin to induce mitophagy in a p62-dependent manner. These results demonstrate a mechanism in which polyubiquitination of a bacterial virulence factor that targets mitochondria directs mitophagy processes to this organelle to prevent its secretion of deleterious ROS.
    DOI:  https://doi.org/10.1038/s41467-024-45961-1
  10. Nat Commun. 2024 Feb 20. 15(1): 1564
    Regulatory T cells use heparanase to access IL-2 bound to extracellular matrix in inflamed tissue.
    Hunter A Martinez, Ievgen Koliesnik, Gernot Kaber, Jacqueline K Reid, Nadine Nagy, Graham Barlow, Ben A Falk, Carlos O Medina, Aviv Hargil, Svenja Zihsler, Israel Vlodavsky, Jin-Ping Li, Magdiel Pérez-Cruz, Sai-Wen Tang, Everett H Meyer, Lucile E Wrenshall, James D Lord, K Christopher Garcia, Theo D Palmer, Lawrence Steinman, Gerald T Nepom, Thomas N Wight, Paul L Bollyky, Hedwich F Kuipers.
      Although FOXP3+ regulatory T cells (Treg) depend on IL-2 produced by other cells for their survival and function, the levels of IL-2 in inflamed tissue are low, making it unclear how Treg access this critical resource. Here, we show that Treg use heparanase (HPSE) to access IL-2 sequestered by heparan sulfate (HS) within the extracellular matrix (ECM) of inflamed central nervous system tissue. HPSE expression distinguishes human and murine Treg from conventional T cells and is regulated by the availability of IL-2. HPSE-/- Treg have impaired stability and function in vivo, including in the experimental autoimmune encephalomyelitis (EAE) mouse model of multiple sclerosis. Conversely, endowing monoclonal antibody-directed chimeric antigen receptor (mAbCAR) Treg with HPSE enhances their ability to access HS-sequestered IL-2 and their ability to suppress neuroinflammation in vivo. Together, these data identify a role for HPSE and the ECM in immune tolerance, providing new avenues for improving Treg-based therapy of autoimmunity.
    DOI:  https://doi.org/10.1038/s41467-024-45012-9
  11. Nat Cell Biol. 2024 Feb 23.
    Metabolic regulation of chemoresistance and immuno-surveillance in AML by SHP-1.
      
    DOI:  https://doi.org/10.1038/s41556-024-01350-w
  12. Nature. 2024 Feb 21.
    IL-10 constrains sphingolipid metabolism to limit inflammation.
    Autumn G York, Mathias H Skadow, Joonseok Oh, Rihao Qu, Quan D Zhou, Wei-Yuan Hsieh, Walter K Mowel, J Richard Brewer, Eleanna Kaffe, Kevin J Williams, Yuval Kluger, Stephen T Smale, Jason M Crawford, Steven J Bensinger, Richard A Flavell.
      Interleukin-10 (IL-10) is a key anti-inflammatory cytokine that can limit immune cell activation and cytokine production in innate immune cell types1. Loss of IL-10 signalling results in life-threatening inflammatory bowel disease in humans and mice-however, the exact mechanism by which IL-10 signalling subdues inflammation remains unclear2-5. Here we find that increased saturated very long chain (VLC) ceramides are critical for the heightened inflammatory gene expression that is a hallmark of IL-10 deficiency. Accordingly, genetic deletion of ceramide synthase 2 (encoded by Cers2), the enzyme responsible for VLC ceramide production, limited the exacerbated inflammatory gene expression programme associated with IL-10 deficiency both in vitro and in vivo. The accumulation of saturated VLC ceramides was regulated by a decrease in metabolic flux through the de novo mono-unsaturated fatty acid synthesis pathway. Restoring mono-unsaturated fatty acid availability to cells deficient in IL-10 signalling limited saturated VLC ceramide production and the associated inflammation. Mechanistically, we find that persistent inflammation mediated by VLC ceramides is largely dependent on sustained activity of REL, an immuno-modulatory transcription factor. Together, these data indicate that an IL-10-driven fatty acid desaturation programme rewires VLC ceramide accumulation and aberrant activation of REL. These studies support the idea that fatty acid homeostasis in innate immune cells serves as a key regulatory node to control pathologic inflammation and suggests that 'metabolic correction' of VLC homeostasis could be an important strategy to normalize dysregulated inflammation caused by the absence of IL-10.
    DOI:  https://doi.org/10.1038/s41586-024-07098-5
  13. Nat Commun. 2024 Feb 22. 15(1): 1646
    M2 macrophages independently promote beige adipogenesis via blocking adipocyte Ets1.
    Suyang Wu, Chen Qiu, Jiahao Ni, Wenli Guo, Jiyuan Song, Xingyin Yang, Yulin Sun, Yanjun Chen, Yunxia Zhu, Xiaoai Chang, Peng Sun, Chunxia Wang, Kai Li, Xiao Han.
      Adipose tissue macrophages can promote beige adipose thermogenesis by altering local sympathetic activity. Here, we perform sympathectomy in mice and further eradicate subcutaneous adipose macrophages and discover that these macrophages have a direct beige-promoting function that is independent of sympathetic system. We further identify adipocyte Ets1 as a vital mediator in this process. The anti-inflammatory M2 macrophages suppress Ets1 expression in adipocytes, transcriptionally activate mitochondrial biogenesis, as well as suppress mitochondrial clearance, thereby increasing the mitochondrial numbers and promoting the beiging process. Male adipocyte Ets1 knock-in mice are completely cold intolerant, whereas male mice lacking Ets1 in adipocytes show enhanced energy expenditure and are resistant to metabolic disorders caused by high-fat-diet. Our findings elucidate a direct communication between M2 macrophages and adipocytes, and uncover a function for Ets1 in responding to macrophages and negatively governing mitochondrial content and beige adipocyte formation.
    DOI:  https://doi.org/10.1038/s41467-024-45899-4
  14. Nat Commun. 2024 Feb 23. 15(1): 1679
    Quantitative live cell imaging of a tauopathy model enables the identification of a polypharmacological drug candidate that restores physiological microtubule interaction.
    Luca Pinzi, Christian Conze, Nicolo Bisi, Gabriele Dalla Torre, Ahmed Soliman, Nanci Monteiro-Abreu, Nataliya I Trushina, Andrea Krusenbaum, Maryam Khodaei Dolouei, Andrea Hellwig, Michael S Christodoulou, Daniele Passarella, Lidia Bakota, Giulio Rastelli, Roland Brandt.
      Tauopathies such as Alzheimer's disease are characterized by aggregation and increased phosphorylation of the microtubule-associated protein tau. Tau's pathological changes are closely linked to neurodegeneration, making tau a prime candidate for intervention. We developed an approach to monitor pathological changes of aggregation-prone human tau in living neurons. We identified 2-phenyloxazole (PHOX) derivatives as putative polypharmacological small molecules that interact with tau and modulate tau kinases. We found that PHOX15 inhibits tau aggregation, restores tau's physiological microtubule interaction, and reduces tau phosphorylation at disease-relevant sites. Molecular dynamics simulations highlight cryptic channel-like pockets crossing tau protofilaments and suggest that PHOX15 binding reduces the protofilament's ability to adopt a PHF-like conformation by modifying a key glycine triad. Our data demonstrate that live-cell imaging of a tauopathy model enables screening of compounds that modulate tau-microtubule interaction and allows identification of a promising polypharmacological drug candidate that simultaneously inhibits tau aggregation and reduces tau phosphorylation.
    DOI:  https://doi.org/10.1038/s41467-024-45851-6
  15. Nat Commun. 2024 Feb 21. 15(1): 1594
    Learning representations for image-based profiling of perturbations.
    Nikita Moshkov, Michael Bornholdt, Santiago Benoit, Matthew Smith, Claire McQuin, Allen Goodman, Rebecca A Senft, Yu Han, Mehrtash Babadi, Peter Horvath, Beth A Cimini, Anne E Carpenter, Shantanu Singh, Juan C Caicedo.
      Measuring the phenotypic effect of treatments on cells through imaging assays is an efficient and powerful way of studying cell biology, and requires computational methods for transforming images into quantitative data. Here, we present an improved strategy for learning representations of treatment effects from high-throughput imaging, following a causal interpretation. We use weakly supervised learning for modeling associations between images and treatments, and show that it encodes both confounding factors and phenotypic features in the learned representation. To facilitate their separation, we constructed a large training dataset with images from five different studies to maximize experimental diversity, following insights from our causal analysis. Training a model with this dataset successfully improves downstream performance, and produces a reusable convolutional network for image-based profiling, which we call Cell Painting CNN. We evaluated our strategy on three publicly available Cell Painting datasets, and observed that the Cell Painting CNN improves performance in downstream analysis up to 30% with respect to classical features, while also being more computationally efficient.
    DOI:  https://doi.org/10.1038/s41467-024-45999-1
  16. Nature. 2024 Feb 21.
    Judith Campisi (1948-2024), cell biologist who explored how cells age.
    Jan Vijg, Jan Hoeijmakers.
      
    Keywords:  Cancer; Cell biology; Medical research
    DOI:  https://doi.org/10.1038/d41586-024-00538-2
  17. Nat Immunol. 2024 Feb 21.
    A mechanism for BCG vaccine cross-protection against pulmonary viral infections.
      
    DOI:  https://doi.org/10.1038/s41590-024-01775-3
  18. Nat Commun. 2024 Feb 19. 15(1): 1508
    A transient protein folding response targets aggregation in the early phase of TDP-43-mediated neurodegeneration.
    Rebecca San Gil, Dana Pascovici, Juliana Venturato, Heledd Brown-Wright, Prachi Mehta, Lidia Madrid San Martin, Jemma Wu, Wei Luan, Yi Kit Chui, Adekunle T Bademosi, Shilpa Swaminathan, Serey Naidoo, Britt A Berning, Amanda L Wright, Sean S Keating, Maurice A Curtis, Richard L M Faull, John D Lee, Shyuan T Ngo, Albert Lee, Marco Morsch, Roger S Chung, Emma Scotter, Leszek Lisowski, Mehdi Mirzaei, Adam K Walker.
      Understanding the mechanisms that drive TDP-43 pathology is integral to combating amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration (FTLD) and other neurodegenerative diseases. Here we generated a longitudinal quantitative proteomic map of the cortex from the cytoplasmic TDP-43 rNLS8 mouse model of ALS and FTLD, and developed a complementary open-access webtool, TDP-map ( https://shiny.rcc.uq.edu.au/TDP-map/ ). We identified distinct protein subsets enriched for diverse biological pathways with temporal alterations in protein abundance, including increases in protein folding factors prior to disease onset. This included increased levels of DnaJ homolog subfamily B member 5, DNAJB5, which also co-localized with TDP-43 pathology in diseased human motor cortex. DNAJB5 over-expression decreased TDP-43 aggregation in cell and cortical neuron cultures, and knockout of Dnajb5 exacerbated motor impairments caused by AAV-mediated cytoplasmic TDP-43 expression in mice. Together, these findings reveal molecular mechanisms at distinct stages of ALS and FTLD progression and suggest that protein folding factors could be protective in neurodegenerative diseases.
    DOI:  https://doi.org/10.1038/s41467-024-45646-9
  19. Nat Metab. 2024 Feb 20.
    Simultaneous targeting of POMC and AgRP neurons.
    Liangyou Rui.
      
    DOI:  https://doi.org/10.1038/s42255-023-00951-3
  20. Nat Commun. 2024 Feb 22. 15(1): 1629
    scCASE: accurate and interpretable enhancement for single-cell chromatin accessibility sequencing data.
    Songming Tang, Xuejian Cui, Rongxiang Wang, Sijie Li, Siyu Li, Xin Huang, Shengquan Chen.
      Single-cell chromatin accessibility sequencing (scCAS) has emerged as a valuable tool for interrogating and elucidating epigenomic heterogeneity and gene regulation. However, scCAS data inherently suffers from limitations such as high sparsity and dimensionality, which pose significant challenges for downstream analyses. Although several methods are proposed to enhance scCAS data, there are still challenges and limitations that hinder the effectiveness of these methods. Here, we propose scCASE, a scCAS data enhancement method based on non-negative matrix factorization which incorporates an iteratively updating cell-to-cell similarity matrix. Through comprehensive experiments on multiple datasets, we demonstrate the advantages of scCASE over existing methods for scCAS data enhancement. The interpretable cell type-specific peaks identified by scCASE can provide valuable biological insights into cell subpopulations. Moreover, to leverage the large compendia of available omics data as a reference, we further expand scCASE to scCASER, which enables the incorporation of external reference data to improve enhancement performance.
    DOI:  https://doi.org/10.1038/s41467-024-46045-w
  21. Nat Commun. 2024 Feb 17. 15(1): 1469
    DIAPH1-MFN2 interaction decreases the endoplasmic reticulum-mitochondrial distance and promotes cardiac injury following myocardial ischemia.
    Lorrie A Kirshenbaum, Rimpy Dhingra, Roberto Bravo-Sagua, Sergio Lavandero.
      
    DOI:  https://doi.org/10.1038/s41467-024-45560-0
  22. Nat Rev Immunol. 2024 Feb 19.
    The regulation and differentiation of regulatory T cells and their dysfunction in autoimmune diseases.
    Tomokazu S Sumida, Nardos T Cheru, David A Hafler.
      The discovery of FOXP3+ regulatory T (Treg) cells as a distinct cell lineage with a central role in regulating immune responses provided a deeper understanding of self-tolerance. The transcription factor FOXP3 serves a key role in Treg cell lineage determination and maintenance, but is not sufficient to enable the full potential of Treg cell suppression, indicating that other factors orchestrate the fine-tuning of Treg cell function. Moreover, FOXP3-independent mechanisms have recently been shown to contribute to Treg cell dysfunction. FOXP3 mutations in humans cause lethal fulminant systemic autoinflammation (IPEX syndrome). However, it remains unclear to what degree Treg cell dysfunction is contributing to the pathophysiology of common autoimmune diseases. In this Review, we discuss the origins of Treg cells in the periphery and the multilayered mechanisms by which Treg cells are induced, as well as the FOXP3-dependent and FOXP3-independent cellular programmes that maintain the suppressive function of Treg cells in humans and mice. Further, we examine evidence for Treg cell dysfunction in the context of common autoimmune diseases such as multiple sclerosis, inflammatory bowel disease, systemic lupus erythematosus and rheumatoid arthritis.
    DOI:  https://doi.org/10.1038/s41577-024-00994-x
  23. Nat Cell Biol. 2024 Feb 20.
    Mapping T cell landscapes in B cell lymphomas.
    Ralf Küppers.
      
    DOI:  https://doi.org/10.1038/s41556-023-01333-3
  24. Nat Commun. 2024 Feb 23. 15(1): 1653
    Runx1+ vascular smooth muscle cells are essential for hematopoietic stem and progenitor cell development in vivo.
    Zaniah N Gonzalez Galofre, Alastair M Kilpatrick, Madalena Marques, Diana Sá da Bandeira, Telma Ventura, Mario Gomez Salazar, Léa Bouilleau, Yvan Marc, Ana B Barbosa, Fiona Rossi, Mariana Beltran, Harmen J G van de Werken, Wilfred F J van IJcken, Neil C Henderson, Stuart J Forbes, Mihaela Crisan.
      Hematopoietic stem cells (HSCs) produce all essential cellular components of the blood. Stromal cell lines supporting HSCs follow a vascular smooth muscle cell (vSMC) differentiation pathway, suggesting that some hematopoiesis-supporting cells originate from vSMC precursors. These pericyte-like precursors were recently identified in the aorta-gonad-mesonephros (AGM) region; however, their role in the hematopoietic development in vivo remains unknown. Here, we identify a subpopulation of NG2+Runx1+ perivascular cells that display a sclerotome-derived vSMC transcriptomic profile. We show that deleting Runx1 in NG2+ cells impairs the hematopoietic development in vivo and causes transcriptional changes in pericytes/vSMCs, endothelial cells and hematopoietic cells in the murine AGM. Importantly, this deletion leads also to a significant reduction of HSC reconstitution potential in the bone marrow in vivo. This defect is developmental, as NG2+Runx1+ cells were not detected in the adult bone marrow, demonstrating the existence of a specialised pericyte population in the HSC-generating niche, unique to the embryo.
    DOI:  https://doi.org/10.1038/s41467-024-44913-z
  25. Nat Commun. 2024 Feb 19. 15(1): 1394
    A single cell atlas of frozen shoulder capsule identifies features associated with inflammatory fibrosis resolution.
    ICECAP Consortium
      Frozen shoulder is a spontaneously self-resolving chronic inflammatory fibrotic human disease, which distinguishes the condition from most fibrotic diseases that are progressive and irreversible. Using single-cell analysis, we identify pro-inflammatory MERTKlowCD48+ macrophages and MERTK + LYVE1 + MRC1+ macrophages enriched for negative regulators of inflammation which co-exist in frozen shoulder capsule tissues. Micro-cultures of patient-derived cells identify integrin-mediated cell-matrix interactions between MERTK+ macrophages and pro-resolving DKK3+ and POSTN+ fibroblasts, suggesting that matrix remodelling plays a role in frozen shoulder resolution. Cross-tissue analysis reveals a shared gene expression cassette between shoulder capsule MERTK+ macrophages and a respective population enriched in synovial tissues of rheumatoid arthritis patients in disease remission, supporting the concept that MERTK+ macrophages mediate resolution of inflammation and fibrosis. Single-cell transcriptomic profiling and spatial analysis of human foetal shoulder tissues identify MERTK + LYVE1 + MRC1+ macrophages and DKK3+ and POSTN+ fibroblast populations analogous to those in frozen shoulder, suggesting that the template to resolve fibrosis is established during shoulder development. Crosstalk between MerTK+ macrophages and pro-resolving DKK3+ and POSTN+ fibroblasts could facilitate resolution of frozen shoulder, providing a basis for potential therapeutic resolution of persistent fibrotic diseases.
    DOI:  https://doi.org/10.1038/s41467-024-45341-9
  26. Nature. 2024 Feb 19.
    Ambitious survey of human diversity yields millions of undiscovered genetic variants.
    Max Kozlov.
      
    Keywords:  Diseases; Genomics; Institutions; Personalized medicine; Research data
    DOI:  https://doi.org/10.1038/d41586-024-00502-0
  27. Mol Cell. 2024 Feb 20. pii: S1097-2765(24)00093-5. [Epub ahead of print]
    Denaturing purifications demonstrate that PRC2 and other widely reported chromatin proteins do not appear to bind directly to RNA in vivo.
    Jimmy K Guo, Mario R Blanco, Ward G Walkup, Grant Bonesteele, Carl R Urbinati, Abhik K Banerjee, Amy Chow, Olivia Ettlin, Mackenzie Strehle, Parham Peyda, Enrique Amaya, Vickie Trinh, Mitchell Guttman.
      Polycomb repressive complex 2 (PRC2) is reported to bind to many RNAs and has become a central player in reports of how long non-coding RNAs (lncRNAs) regulate gene expression. Yet, there is a growing discrepancy between the biochemical evidence supporting specific lncRNA-PRC2 interactions and functional evidence demonstrating that PRC2 is often dispensable for lncRNA function. Here, we revisit the evidence supporting RNA binding by PRC2 and show that many reported interactions may not occur in vivo. Using denaturing purification of in vivo crosslinked RNA-protein complexes in human and mouse cell lines, we observe a loss of detectable RNA binding to PRC2 and chromatin-associated proteins previously reported to bind RNA (CTCF, YY1, and others), despite accurately mapping bona fide RNA-binding sites across others (SPEN, TET2, and others). Taken together, these results argue for a critical re-evaluation of the broad role of RNA binding to orchestrate various chromatin regulatory mechanisms.
    Keywords:  CLIP; PRC2; RNA; RNA-binding proteins; chromatin
    DOI:  https://doi.org/10.1016/j.molcel.2024.01.026
  28. Nat Med. 2024 Feb 22.
    Longitudinal analysis shows how microbiome changes might influence responses to immune checkpoint blockade.
      
    DOI:  https://doi.org/10.1038/s41591-024-02830-0
  29. Nature. 2024 Feb 23.
    How we boosted female faculty numbers in male-dominated departments.
    Dom Byrne.
      
    DOI:  https://doi.org/10.1038/d41586-024-00212-7
  30. Cell Metab. 2024 Feb 12. pii: S1550-4131(24)00015-9. [Epub ahead of print]
    IgG is an aging factor that drives adipose tissue fibrosis and metabolic decline.
    Lexiang Yu, Qianfen Wan, Qiongming Liu, Yong Fan, Qiuzhong Zhou, Alicja A Skowronski, Summer Wang, Zhengping Shao, Chen-Yu Liao, Lei Ding, Brian K Kennedy, Shan Zha, Jianwen Que, Charles A LeDuc, Lei Sun, Liheng Wang, Li Qiang.
      Aging is underpinned by pronounced metabolic decline; however, the drivers remain obscure. Here, we report that IgG accumulates during aging, particularly in white adipose tissue (WAT), to impair adipose tissue function and metabolic health. Caloric restriction (CR) decreases IgG accumulation in WAT, whereas replenishing IgG counteracts CR's metabolic benefits. IgG activates macrophages via Ras signaling and consequently induces fibrosis in WAT through the TGF-β/SMAD pathway. Consistently, B cell null mice are protected from aging-associated WAT fibrosis, inflammation, and insulin resistance, unless exposed to IgG. Conditional ablation of the IgG recycling receptor, neonatal Fc receptor (FcRn), in macrophages prevents IgG accumulation in aging, resulting in prolonged healthspan and lifespan. Further, targeting FcRn by antisense oligonucleotide restores WAT integrity and metabolic health in aged mice. These findings pinpoint IgG as a hidden culprit in aging and enlighten a novel strategy to rejuvenate metabolic health.
    Keywords:  IgG; adipose tissue; aging; fibrosis; metabolic dysfunction
    DOI:  https://doi.org/10.1016/j.cmet.2024.01.015
  31. Nat Commun. 2024 Feb 21. 15(1): 1496
    Exosomes define a local and systemic communication network in healthy pancreas and pancreatic ductal adenocarcinoma.
    Bárbara Adem, Nuno Bastos, Carolina F Ruivo, Sara Sousa-Alves, Carolina Dias, Patrícia F Vieira, Inês A Batista, Bruno Cavadas, Dieter Saur, José C Machado, Dawen Cai, Sonia A Melo.
      Pancreatic ductal adenocarcinoma (PDAC), a lethal disease, requires a grasp of its biology for effective therapies. Exosomes, implicated in cancer, are poorly understood in living systems. Here we use the genetically engineered mouse model (ExoBow) to map the spatiotemporal distribution of exosomes from healthy and PDAC pancreas in vivo to determine their biological significance. We show that, within the PDAC microenvironment, cancer cells establish preferential communication routes through exosomes with cancer associated fibroblasts and endothelial cells. The latter being a conserved event in the healthy pancreas. Inhibiting exosomes secretion in both scenarios enhances angiogenesis, underscoring their contribution to vascularization and to cancer. Inter-organ communication is significantly increased in PDAC with specific organs as most frequent targets of exosomes communication occurring in health with the thymus, bone-marrow, brain, and intestines, and in PDAC with the kidneys, lungs and thymus. In sum, we find that exosomes mediate an organized intra- and inter- pancreas communication network with modulatory effects in vivo.
    DOI:  https://doi.org/10.1038/s41467-024-45753-7
  32. Nat Immunol. 2024 Feb 20.
    A nasal vaccine elicits protective CD8+ T cell immunity against antigen shifted SARS-CoV-2 virus.
      
    DOI:  https://doi.org/10.1038/s41590-024-01744-w
  33. Nat Commun. 2024 Feb 21. 15(1): 1568
    Meiotic protein SYCP2 confers resistance to DNA-damaging agents through R-loop-mediated DNA repair.
    Yumin Wang, Boya Gao, Luyuan Zhang, Xudong Wang, Xiaolan Zhu, Haibo Yang, Fengqi Zhang, Xueping Zhu, Badi Zhou, Sean Yao, Aiko Nagayama, Sanghoon Lee, Jian Ouyang, Siang-Boon Koh, Eric L Eisenhauer, Dominique Zarrella, Kate Lu, Bo R Rueda, Lee Zou, Xiaofeng A Su, Oladapo Yeku, Leif W Ellisen, Xiao-Song Wang, Li Lan.
      Drugs targeting the DNA damage response (DDR) are widely used in cancer therapy, but resistance to these drugs remains a major clinical challenge. Here, we show that SYCP2, a meiotic protein in the synaptonemal complex, is aberrantly and commonly expressed in breast and ovarian cancers and associated with broad resistance to DDR drugs. Mechanistically, SYCP2 enhances the repair of DNA double-strand breaks (DSBs) through transcription-coupled homologous recombination (TC-HR). SYCP2 promotes R-loop formation at DSBs and facilitates RAD51 recruitment independently of BRCA1. SYCP2 loss impairs RAD51 localization, reduces TC-HR, and renders tumors sensitive to PARP and topoisomerase I (TOP1) inhibitors. Furthermore, our studies of two clinical cohorts find that SYCP2 overexpression correlates with breast cancer resistance to antibody-conjugated TOP1 inhibitor and ovarian cancer resistance to platinum treatment. Collectively, our data suggest that SYCP2 confers cancer cell resistance to DNA-damaging agents by stimulating R-loop-mediated DSB repair, offering opportunities to improve DDR therapy.
    DOI:  https://doi.org/10.1038/s41467-024-45693-2
  34. Sci Signal. 2024 Feb 20. 17(824): eadg9256
    Designer high-density lipoprotein particles enhance endothelial barrier function and suppress inflammation.
    Yueh-Chien Lin, Steven Swendeman, Irina S Moreira, Avishek Ghosh, Andrew Kuo, Nícia Rosário-Ferreira, Shihui Guo, Alan Culbertson, Michel V Levesque, Andreane Cartier, Takahiro Seno, Alec Schmaier, Sylvain Galvani, Asuka Inoue, Samir M Parikh, Garret A FitzGerald, David Zurakowski, Maofu Liao, Robert Flaumenhaft, Zeynep H Gümüş, Timothy Hla.
      High-density lipoprotein (HDL) nanoparticles promote endothelial cell (EC) function and suppress inflammation, but their utility in treating EC dysfunction has not been fully explored. Here, we describe a fusion protein named ApoA1-ApoM (A1M) consisting of apolipoprotein A1 (ApoA1), the principal structural protein of HDL that forms lipid nanoparticles, and ApoM, a chaperone for the bioactive lipid sphingosine 1-phosphate (S1P). A1M forms HDL-like particles, binds to S1P, and is signaling competent. Molecular dynamics simulations showed that the S1P-bound ApoM moiety in A1M efficiently activated EC surface receptors. Treatment of human umbilical vein ECs with A1M-S1P stimulated barrier function either alone or cooperatively with other barrier-enhancing molecules, including the stable prostacyclin analog iloprost, and suppressed cytokine-induced inflammation. A1M-S1P injection into mice during sterile inflammation suppressed neutrophil influx and inflammatory mediator secretion. Moreover, systemic A1M administration led to a sustained increase in circulating HDL-bound S1P and suppressed inflammation in a murine model of LPS-induced endotoxemia. We propose that A1M administration may enhance vascular endothelial barrier function, suppress cytokine storm, and promote resilience of the vascular endothelium.
    DOI:  https://doi.org/10.1126/scisignal.adg9256
  35. Nature. 2024 Feb 21.
    The UFM1 E3 ligase recognizes and releases 60S ribosomes from ER translocons.
    Linda Makhlouf, Joshua J Peter, Helge M Magnussen, Rohan Thakur, David Millrine, Thomas C Minshull, Grace Harrison, Joby Varghese, Frederic Lamoliatte, Martina Foglizzo, Thomas Macartney, Antonio N Calabrese, Elton Zeqiraj, Yogesh Kulathu.
      Stalled ribosomes at the endoplasmic reticulum (ER) are covalently modified with the ubiquitin-like protein UFM1 on the 60S ribosomal subunit protein RPL26 (also known as uL24)1,2. This modification, which is known as UFMylation, is orchestrated by the UFM1 ribosome E3 ligase (UREL) complex, comprising UFL1, UFBP1 and CDK5RAP3 (ref. 3). However, the catalytic mechanism of UREL and the functional consequences of UFMylation are unclear. Here we present cryo-electron microscopy structures of UREL bound to 60S ribosomes, revealing the basis of its substrate specificity. UREL wraps around the 60S subunit to form a C-shaped clamp architecture that blocks the tRNA-binding sites at one end, and the peptide exit tunnel at the other. A UFL1 loop inserts into and remodels the peptidyl transferase centre. These features of UREL suggest a crucial function for UFMylation in the release and recycling of stalled or terminated ribosomes from the ER membrane. In the absence of functional UREL, 60S-SEC61 translocon complexes accumulate at the ER membrane, demonstrating that UFMylation is necessary for releasing SEC61 from 60S subunits. Notably, this release is facilitated by a functional switch of UREL from a 'writer' to a 'reader' module that recognizes its product-UFMylated 60S ribosomes. Collectively, we identify a fundamental role for UREL in dissociating 60S subunits from the SEC61 translocon and the basis for UFMylation in regulating protein homeostasis at the ER.
    DOI:  https://doi.org/10.1038/s41586-024-07093-w
  36. Nat Commun. 2024 Feb 20. 15(1): 1542
    Functional plasticity of glutamatergic neurons of medullary reticular nuclei after spinal cord injury in mice.
    Maxime Lemieux, Narges Karimi, Frederic Bretzner.
      Spinal cord injury disrupts the descending command from the brain and causes a range of motor deficits. Here, we use optogenetic tools to investigate the functional plasticity of the glutamatergic reticulospinal drive of the medullary reticular formation after a lateral thoracic hemisection in female mice. Sites evoking stronger excitatory descending drive in intact conditions are the most impaired after injury, whereas those associated with a weaker drive are potentiated. After lesion, pro- and anti-locomotor activities (that is, initiation/acceleration versus stop/deceleration) are overall preserved. Activating the descending reticulospinal drive improves stepping ability on a flat surface of chronically impaired injured mice, and its priming enhances recovery of skilled locomotion on a horizontal ladder. This study highlights the resilience and capacity for reorganization of the glutamatergic reticulospinal command after injury, along with its suitability as a therapeutical target to promote functional recovery.
    DOI:  https://doi.org/10.1038/s41467-024-45300-4
  37. Nature. 2024 Feb 21.
    Targeted protein degradation via intramolecular bivalent glues.
    Oliver Hsia, Matthias Hinterndorfer, Angus D Cowan, Kentaro Iso, Tasuku Ishida, Ramasubramanian Sundaramoorthy, Mark A Nakasone, Hana Imrichova, Caroline Schätz, Andrea Rukavina, Koraljka Husnjak, Martin Wegner, Alejandro Correa-Sáez, Conner Craigon, Ryan Casement, Chiara Maniaci, Andrea Testa, Manuel Kaulich, Ivan Dikic, Georg E Winter, Alessio Ciulli.
      Targeted protein degradation is a pharmacological modality that is based on the induced proximity of an E3 ubiquitin ligase and a target protein to promote target ubiquitination and proteasomal degradation. This has been achieved either via proteolysis-targeting chimeras (PROTACs)-bifunctional compounds composed of two separate moieties that individually bind the target and E3 ligase, or via molecular glues that monovalently bind either the ligase or the target1-4. Here, using orthogonal genetic screening, biophysical characterization and structural reconstitution, we investigate the mechanism of action of bifunctional degraders of BRD2 and BRD4, termed intramolecular bivalent glues (IBGs), and find that instead of connecting target and ligase in trans as PROTACs do, they simultaneously engage and connect two adjacent domains of the target protein in cis. This conformational change 'glues' BRD4 to the E3 ligases DCAF11 or DCAF16, leveraging intrinsic target-ligase affinities that do not translate to BRD4 degradation in the absence of compound. Structural insights into the ternary BRD4-IBG1-DCAF16 complex guided the rational design of improved degraders of low picomolar potency. We thus introduce a new modality in targeted protein degradation, which works by bridging protein domains in cis to enhance surface complementarity with E3 ligases for productive ubiquitination and degradation.
    DOI:  https://doi.org/10.1038/s41586-024-07089-6
  38. Mol Cell. 2024 Feb 09. pii: S1097-2765(24)00056-X. [Epub ahead of print]
    Transcription factor exchange enables prolonged transcriptional bursts.
    Wim Pomp, Joseph V W Meeussen, Tineke L Lenstra.
      Single-molecule imaging inside living cells has revealed that transcription factors (TFs) bind to DNA transiently, but a long-standing question is how this transient binding is related to transcription activation. Here, we devised a microscopy method to simultaneously measure transient TF binding at a single locus and the effect of these binding events on transcription. We show that DNA binding of the yeast TF Gal4 activates transcription of a target gene within a few seconds, with at least ∼20% efficiency and with a high initiation rate of ∼1 RNA/s. Gal4 DNA dissociation decreases transcription rapidly. Moreover, at a gene with multiple binding sites, individual Gal4 molecules only rarely stay bound throughout the entire burst but instead frequently exchange during a burst to increase the transcriptional burst duration. Our results suggest a mechanism for enhancer regulation in more complex eukaryotes, where TF cooperativity and exchange enable robust and responsive transcription regulation.
    Keywords:  DNA binding kinetics; cooperativity; single-molecule imaging; transcription factor; transcriptional bursting
    DOI:  https://doi.org/10.1016/j.molcel.2024.01.020
  39. Nat Commun. 2024 Feb 17. 15(1): 1465
    Spatiotemporal and direct capturing global substrates of lysine-modifying enzymes in living cells.
    Hao Hu, Wei Hu, An-Di Guo, Linhui Zhai, Song Ma, Hui-Jun Nie, Bin-Shan Zhou, Tianxian Liu, Xinglong Jia, Xing Liu, Xuebiao Yao, Minjia Tan, Xiao-Hua Chen.
      Protein-modifying enzymes regulate the dynamics of myriad post-translational modification (PTM) substrates. Precise characterization of enzyme-substrate associations is essential for the molecular basis of cellular function and phenotype. Methods for direct capturing global substrates of protein-modifying enzymes in living cells are with many challenges, and yet largely unexplored. Here, we report a strategy to directly capture substrates of lysine-modifying enzymes via PTM-acceptor residue crosslinking in living cells, enabling global profiling of substrates of PTM-enzymes and validation of PTM-sites in a straightforward manner. By integrating enzymatic PTM-mechanisms, and genetically encoding residue-selective photo-crosslinker into PTM-enzymes, our strategy expands the substrate profiles of both bacterial and mammalian lysine acylation enzymes, including bacterial lysine acylases PatZ, YiaC, LplA, TmcA, and YjaB, as well as mammalian acyltransferases GCN5 and Tip60, leading to discovery of distinct yet functionally important substrates and acylation sites. The concept of direct capturing substrates of PTM-enzymes via residue crosslinking may extend to the other types of amino acid residues beyond lysine, which has the potential to facilitate the investigation of diverse types of PTMs and substrate-enzyme interactive proteomics.
    DOI:  https://doi.org/10.1038/s41467-024-45765-3
  40. Nat Rev Immunol. 2024 Feb 19.
    Mechanistic insights from inflammasome structures.
    Jianing Fu, Kate Schroder, Hao Wu.
      Inflammasomes are supramolecular complexes that form in the cytosol in response to pathogen-associated and damage-associated stimuli, as well as other danger signals that perturb cellular homoeostasis, resulting in host defence responses in the form of cytokine release and programmed cell death (pyroptosis). Inflammasome activity is closely associated with numerous human disorders, including rare genetic syndromes of autoinflammation, cardiovascular diseases, neurodegeneration and cancer. In recent years, a range of inflammasome components and their functions have been discovered, contributing to our knowledge of the overall machinery. Here, we review the latest advances in inflammasome biology from the perspective of structural and mechanistic studies. We focus on the most well-studied components of the canonical inflammasome - NAIP-NLRC4, NLRP3, NLRP1, CARD8 and caspase-1 - as well as caspase-4, caspase-5 and caspase-11 of the noncanonical inflammasome, and the inflammasome effectors GSDMD and NINJ1. These structural studies reveal important insights into how inflammasomes are assembled and regulated, and how they elicit the release of IL-1 family cytokines and induce membrane rupture in pyroptosis.
    DOI:  https://doi.org/10.1038/s41577-024-00995-w
  41. EMBO J. 2024 Feb 20.
    A mosquito salivary protein-driven influx of myeloid cells facilitates flavivirus transmission.
    Zhaoyang Wang, Kaixiao Nie, Yan Liang, Jichen Niu, Xi Yu, Oujia Zhang, Long Liu, Xiaolu Shi, Yibaina Wang, Xuechun Feng, Yibin Zhu, Penghua Wang, Gong Cheng.
      Mosquitoes transmit many disease-relevant flaviviruses. Efficient viral transmission to mammalian hosts requires mosquito salivary factors. However, the specific salivary components facilitating viral transmission and their mechanisms of action remain largely unknown. Here, we show that a female mosquito salivary gland-specific protein, here named A. aegypti Neutrophil Recruitment Protein (AaNRP), facilitates the transmission of Zika and dengue viruses. AaNRP promotes a rapid influx of neutrophils, followed by virus-susceptible myeloid cells toward mosquito bite sites, which facilitates establishment of local infection and systemic dissemination. Mechanistically, AaNRP engages TLR1 and TLR4 of skin-resident macrophages and activates MyD88-dependent NF-κB signaling to induce the expression of neutrophil chemoattractants. Inhibition of MyD88-NF-κB signaling with the dietary phytochemical resveratrol reduces AaNRP-mediated enhancement of flavivirus transmission by mosquitoes. These findings exemplify how salivary components can aid viral transmission, and suggest a potential prophylactic target.
    Keywords:  Flavivirus; Mosquito salivary protein; NF-κB; Neutrophil; Toll-like receptor
    DOI:  https://doi.org/10.1038/s44318-024-00056-x
  42. Nat Commun. 2024 Feb 20. 15(1): 1309
    Fasting-mimicking diet causes hepatic and blood markers changes indicating reduced biological age and disease risk.
    Sebastian Brandhorst, Morgan E Levine, Min Wei, Mahshid Shelehchi, Todd E Morgan, Krishna S Nayak, Tanya Dorff, Kurt Hong, Eileen M Crimmins, Pinchas Cohen, Valter D Longo.
      In mice, periodic cycles of a fasting mimicking diet (FMD) protect normal cells while killing damaged cells including cancer and autoimmune cells, reduce inflammation, promote multi-system regeneration, and extend longevity. Here, we performed secondary and exploratory analysis of blood samples from a randomized clinical trial (NCT02158897) and show that 3 FMD cycles in adult study participants are associated with reduced insulin resistance and other pre-diabetes markers, lower hepatic fat (as determined by magnetic resonance imaging) and increased lymphoid to myeloid ratio: an indicator of immune system age. Based on a validated measure of biological age predictive of morbidity and mortality, 3 FMD cycles were associated with a decrease of 2.5 years in median biological age, independent of weight loss. Nearly identical findings resulted from  a second clinical study (NCT04150159). Together these results provide initial support for beneficial effects of the FMD on multiple cardiometabolic risk factors and biomarkers of biological age.
    DOI:  https://doi.org/10.1038/s41467-024-45260-9
  43. Nat Commun. 2024 Feb 21. 15(1): 1584
    Integrating single-cell and spatially resolved transcriptomic strategies to survey the astrocyte response to stroke in male mice.
    Erica Y Scott, Nickie Safarian, Daniela Lozano Casasbuenas, Michael Dryden, Teodora Tockovska, Shawar Ali, Jiaxi Peng, Emerson Daniele, Isabel Nie Xin Lim, K W Annie Bang, Shreejoy Tripathy, Scott A Yuzwa, Aaron R Wheeler, Maryam Faiz.
      Astrocytes, a type of glial cell in the central nervous system (CNS), adopt diverse states in response to injury that are influenced by their location relative to the insult. Here, we describe a platform for spatially resolved, single-cell transcriptomics and proteomics, called tDISCO (tissue-digital microfluidic isolation of single cells for -Omics). We use tDISCO alongside two high-throughput platforms for spatial (Visium) and single-cell transcriptomics (10X Chromium) to examine the heterogeneity of the astrocyte response to a cortical ischemic stroke in male mice. We show that integration of Visium and 10X Chromium datasets infers two astrocyte populations, proximal or distal to the injury site, while tDISCO determines the spatial boundaries and molecular profiles that define these populations. We find that proximal astrocytes show differences in lipid shuttling, with enriched expression of Apoe and Fabp5. Our datasets provide a resource for understanding the roles of astrocytes in stroke and showcase the utility of tDISCO for hypothesis-driven, spatially resolved single-cell experiments.
    DOI:  https://doi.org/10.1038/s41467-024-45821-y
  44. J Exp Med. 2024 Apr 01. pii: e20232136. [Epub ahead of print]221(4):
    Cellular senescence: Neither irreversible nor reversible.
    Maurice Reimann, Soyoung Lee, Clemens A Schmitt.
      Cellular senescence is a critical stress response program implicated in embryonic development, wound healing, aging, and immunity, and it backs up apoptosis as an ultimate cell-cycle exit mechanism. In analogy to replicative exhaustion of telomere-eroded cells, premature types of senescence-referring to oncogene-, therapy-, or virus-induced senescence-are widely considered irreversible growth arrest states as well. We discuss here that entry into full-featured senescence is not necessarily a permanent endpoint, but dependent on essential maintenance components, potentially transient. Unlike a binary state switch, we view senescence with its extensive epigenomic reorganization, profound cytomorphological remodeling, and distinctive metabolic rewiring rather as a journey toward a full-featured arrest condition of variable strength and depth. Senescence-underlying maintenance-essential molecular mechanisms may allow cell-cycle reentry if not continuously provided. Importantly, senescent cells that resumed proliferation fundamentally differ from those that never entered senescence, and hence would not reflect a reversion but a dynamic progression to a post-senescent state that comes with distinct functional and clinically relevant ramifications.
    DOI:  https://doi.org/10.1084/jem.20232136
  45. Nat Commun. 2024 Feb 23. 15(1): 1674
    Bacteria employ lysine acetylation of transcriptional regulators to adapt gene expression to cellular metabolism.
    Magdalena Kremer, Sabrina Schulze, Nadja Eisenbruch, Felix Nagel, Robert Vogt, Leona Berndt, Babett Dörre, Gottfried J Palm, Jens Hoppen, Britta Girbardt, Dirk Albrecht, Susanne Sievers, Mihaela Delcea, Ulrich Baumann, Karin Schnetz, Michael Lammers.
      The Escherichia coli TetR-related transcriptional regulator RutR is involved in the coordination of pyrimidine and purine metabolism. Here we report that lysine acetylation modulates RutR function. Applying the genetic code expansion concept, we produced site-specifically lysine-acetylated RutR proteins. The crystal structure of lysine-acetylated RutR reveals how acetylation switches off RutR-DNA-binding. We apply the genetic code expansion concept in E. coli in vivo revealing the consequences of RutR acetylation on the transcriptional level. We propose a model in which RutR acetylation follows different kinetic profiles either reacting non-enzymatically with acetyl-phosphate or enzymatically catalysed by the lysine acetyltransferases PatZ/YfiQ and YiaC. The NAD+-dependent sirtuin deacetylase CobB reverses enzymatic and non-enzymatic acetylation of RutR playing a dual regulatory and detoxifying role. By detecting cellular acetyl-CoA, NAD+ and acetyl-phosphate, bacteria apply lysine acetylation of transcriptional regulators to sense the cellular metabolic state directly adjusting gene expression to changing environmental conditions.
    DOI:  https://doi.org/10.1038/s41467-024-46039-8
  46. Nat Cell Biol. 2024 Feb 22.
    Drosophila TMEM63 and mouse TMEM63A are lysosomal mechanosensory ion channels.
    Kai Li, Yanmeng Guo, Yayu Wang, Ruijun Zhu, Wei Chen, Tong Cheng, Xiaofan Zhang, Yinjun Jia, Ting Liu, Wei Zhang, Lily Yeh Jan, Yuh Nung Jan.
      Cells sense physical forces and convert them into electrical or chemical signals, a process known as mechanotransduction. Whereas extensive studies focus on mechanotransduction at the plasma membrane, little is known about whether and how intracellular organelles sense mechanical force and the physiological functions of organellar mechanosensing. Here we identify the Drosophila TMEM63 (DmTMEM63) ion channel as an intrinsic mechanosensor of the lysosome, a major degradative organelle. Endogenous DmTMEM63 proteins localize to lysosomes, mediate lysosomal mechanosensitivity and modulate lysosomal morphology and function. Tmem63 mutant flies exhibit impaired lysosomal degradation, synaptic loss, progressive motor deficits and early death, with some of these mutant phenotypes recapitulating symptoms of TMEM63-associated human diseases. Importantly, mouse TMEM63A mediates lysosomal mechanosensitivity in Neuro-2a cells, indicative of functional conservation in mammals. Our findings reveal DmTMEM63 channel function in lysosomes and its physiological roles in vivo and provide a molecular basis to explore the mechanosensitive process in subcellular organelles.
    DOI:  https://doi.org/10.1038/s41556-024-01353-7
  47. Nat Commun. 2024 Feb 21. 15(1): 1608
    Global evaluation of lineage-specific human papillomavirus capsid antigenicity using antibodies elicited by natural infection.
    Gathoni Kamuyu, Filomeno Coelho da Silva, Vanessa Tenet, John Schussler, Anna Godi, Rolando Herrero, Carolina Porras, Lisa Mirabello, John T Schiller, Mónica S Sierra, Aimée R Kreimer, Gary M Clifford, Simon Beddows.
      Human Papillomavirus (HPV) type variants have been classified into lineages and sublineages based upon their whole genome sequence. Here we have examined the specificity of antibodies generated following natural infection with lineage variants of oncogenic types (HPV16, 18, 31, 33, 45, 52 and 58) by testing serum samples assembled from existing archives from women residing in Africa, The Americas, Asia or Europe against representative lineage-specific pseudoviruses for each genotype. We have subjected the resulting neutralizing antibody data to antigenic clustering methods and created relational antigenic profiles for each genotype to inform the delineation of lineage-specific serotypes. For most genotypes, there was evidence of differential recognition of lineage-specific antigens and in some cases of a sufficient magnitude to suggest that some lineages should be considered antigenically distinct within their respective genotypes. These data provide compelling evidence for a degree of lineage specificity within the humoral immune response following natural infection with oncogenic HPV.
    DOI:  https://doi.org/10.1038/s41467-024-45807-w
  48. Nat Metab. 2024 Feb 20.
    MCT1 helps brown fat suck up succinate.
    Jens Lund, Marie Sophie Isidor, Zachary Gerhart-Hines.
      
    DOI:  https://doi.org/10.1038/s42255-024-00979-z
  49. Nat Neurosci. 2024 Feb 22.
    Leaky blood-brain barrier in long-COVID-associated brain fog.
      
    DOI:  https://doi.org/10.1038/s41593-024-01577-8
  50. Nat Commun. 2024 Feb 20. 15(1): 1534
    Chronic endoplasmic reticulum stress in myotonic dystrophy type 2 promotes autoimmunity via mitochondrial DNA release.
    Sarah Rösing, Fabian Ullrich, Susann Meisterfeld, Franziska Schmidt, Laura Mlitzko, Marijana Croon, Ryan G Nattrass, Nadia Eberl, Julia Mahlberg, Martin Schlee, Anja Wieland, Philipp Simon, Daniel Hilbig, Ulrike Reuner, Alexander Rapp, Julia Bremser, Peter Mirtschink, Stephan Drukewitz, Thomas Zillinger, Stefan Beissert, Katrin Paeschke, Gunther Hartmann, Aleksandra Trifunovic, Eva Bartok, Claudia Günther.
      Myotonic dystrophy type 2 (DM2) is a tetranucleotide CCTG repeat expansion disease associated with an increased prevalence of autoimmunity. Here, we identified an elevated type I interferon (IFN) signature in peripheral blood mononuclear cells and primary fibroblasts of DM2 patients as a trigger of chronic immune stimulation. Although RNA-repeat accumulation was prevalent in the cytosol of DM2-patient fibroblasts, type-I IFN release did not depend on innate RNA immune sensors but rather the DNA sensor cGAS and the prevalence of mitochondrial DNA (mtDNA) in the cytoplasm. Sublethal mtDNA release was promoted by a chronic activation of the ATF6 branch of the unfolded protein response (UPR) in reaction to RNA-repeat accumulation and non-AUG translated tetrapeptide expansion proteins. ATF6-dependent mtDNA release and resulting cGAS/STING activation could also be recapitulated in human THP-1 monocytes exposed to chronic endoplasmic reticulum (ER) stress. Altogether, our study demonstrates a novel mechanism by which large repeat expansions cause chronic endoplasmic reticulum stress and associated mtDNA leakage. This mtDNA is, in turn, sensed by the cGAS/STING pathway and induces a type-I IFN response predisposing to autoimmunity. Elucidating this pathway reveals new potential therapeutic targets for autoimmune disorders associated with repeat expansion diseases.
    DOI:  https://doi.org/10.1038/s41467-024-45535-1
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