bims-nimamd Biomed News
on Neuroimmunity and neuroinflammation in ageing and metabolic disease
Issue of 2023–11–05
forty papers selected by
Fawaz Alzaïd, Sorbonne Université
  1. The counterintuitive implications of superspreading diseases.
  2. Structural titration reveals Ca2+-dependent conformational landscape of the IP3 receptor.
  3. Genome-wide association analysis of plasma lipidome identifies 495 genetic associations.
  4. Striatum-projecting prefrontal cortex neurons support working memory maintenance.
  5. Stress-induced red nucleus attenuation induces anxiety-like behavior and lymph node CCL5 secretion.
  6. XMAP: Cross-population fine-mapping by leveraging genetic diversity and accounting for confounding bias.
  7. Inhibition of glycolysis-driven immunosuppression with a nano-assembly enhances response to immune checkpoint blockade therapy in triple negative breast cancer.
  8. eQTL mapping in fetal-like pancreatic progenitor cells reveals early developmental insights into diabetes risk.
  9. Cholesterol mediated ferroptosis suppression reveals essential roles of Coenzyme Q and squalene.
  10. Phospholipid modifier PLAAT3 links defective PPARγ-dependent signaling to lipodystrophy.
  11. Dengue is spreading in Europe: how worried should we be?
  12. Audio long read: Why BMI is flawed - and how to redefine obesity.
  13. Structural basis for stabilisation of the RAD51 nucleoprotein filament by BRCA2.
  14. DIAPH1-MFN2 interaction regulates mitochondria-SR/ER contact and modulates ischemic/hypoxic stress.
  15. ARF1 prevents aberrant type I interferon induction by regulating STING activation and recycling.
  16. Hepatocyte FBXW7-dependent activity of nutrient-sensing nuclear receptors controls systemic energy homeostasis and NASH progression in male mice.
  17. A neurodegeneration checkpoint mediated by REST protects against the onset of Alzheimer's disease.
  18. Self-promoted electroactive biomimetic mineralized scaffolds for bacteria-infected bone regeneration.
  19. Microglia-mediated demyelination protects against CD8+ T cell-driven axon degeneration in mice carrying PLP defects.
  20. A phosphoinositide switch mediates exocyst recruitment to multivesicular endosomes for exosome secretion.
  21. Regulatory T cells shield muscle mitochondria from interferon-γ-mediated damage to promote the beneficial effects of exercise.
  22. A pan-tissue survey of mosaic chromosomal alterations in 948 individuals.
  23. Antigen presentation by B cells enables epitope spreading across an MHC barrier.
  24. Deep brain stimulation of thalamic nucleus reuniens promotes neuronal and cognitive resilience in an Alzheimer's disease mouse model.
  25. UNC-49 is a redox-sensitive GABAA receptor that regulates the mitochondrial unfolded protein response cell nonautonomously.
  26. Farnesoid X receptor activation by bile acids suppresses lipid peroxidation and ferroptosis.
  27. A PPARγ/long noncoding RNA axis regulates adipose thermoneutral remodeling in mice.
  28. Lateral hypothalamic proenkephalin neurons drive threat-induced overeating associated with a negative emotional state.
  29. Glioma synapses recruit mechanisms of adaptive plasticity.
  30. Divergent mechanisms of inflammasome activation in neutrophil early response and inflammation.
  31. Age-related dysregulation of homeostatic control in neuronal microcircuits.
  32. A genetic atlas of the human blood proteome.
  33. An in situ dual-anchoring strategy for enhanced immobilization of PD-L1 to treat autoimmune diseases.
  34. Ventral striatal islands of Calleja neurons bidirectionally mediate depression-like behaviors in mice.
  35. CD8 T cell tolerance results from eviction of immature autoreactive cells from the thymus.
  36. Cholesterol regulates insulin-induced mTORC1 signaling.
  37. 4E-BP1-dependent translation in nociceptors controls mechanical hypersensitivity via TRIM32/type I interferon signaling.
  38. Follicle-stimulating hormone orchestrates glucose-stimulated insulin secretion of pancreatic islets.
  39. Self-reported childhood family adversity is linked to an attenuated gain of trust during adolescence.
  40. Glycation-driven matrix crosslinking in cirrhosis.
  1. Nat Commun. 2023 Oct 31. 14(1): 6954
    The counterintuitive implications of superspreading diseases.
    Bjarke Frost Nielsen, Kim Sneppen, Lone Simonsen.
      
    DOI:  https://doi.org/10.1038/s41467-023-42612-9
  2. Nat Commun. 2023 10 28. 14(1): 6897
    Structural titration reveals Ca2+-dependent conformational landscape of the IP3 receptor.
    Navid Paknejad, Vinay Sapuru, Richard K Hite.
      Inositol 1,4,5-trisphosphate receptors (IP3Rs) are endoplasmic reticulum Ca2+ channels whose biphasic dependence on cytosolic Ca2+ gives rise to Ca2+ oscillations that regulate fertilization, cell division and cell death. Despite the critical roles of IP3R-mediated Ca2+ responses, the structural underpinnings of the biphasic Ca2+ dependence that underlies Ca2+ oscillations are incompletely understood. Here, we collect cryo-EM images of an IP3R with Ca2+ concentrations spanning five orders of magnitude. Unbiased image analysis reveals that Ca2+ binding does not explicitly induce conformational changes but rather biases a complex conformational landscape consisting of resting, preactivated, activated, and inhibited states. Using particle counts as a proxy for relative conformational free energy, we demonstrate that Ca2+ binding at a high-affinity site allows IP3Rs to activate by escaping a low-energy resting state through an ensemble of preactivated states. At high Ca2+ concentrations, IP3Rs preferentially enter an inhibited state stabilized by a second, low-affinity Ca2+ binding site. Together, these studies provide a mechanistic basis for the biphasic Ca2+-dependence of IP3R channel activity.
    DOI:  https://doi.org/10.1038/s41467-023-42707-3
  3. Nat Commun. 2023 Oct 31. 14(1): 6934
    Genome-wide association analysis of plasma lipidome identifies 495 genetic associations.
    FinnGen
      The human plasma lipidome captures risk for cardiometabolic diseases. To discover new lipid-associated variants and understand the link between lipid species and cardiometabolic disorders, we perform univariate and multivariate genome-wide analyses of 179 lipid species in 7174 Finnish individuals. We fine-map the associated loci, prioritize genes, and examine their disease links in 377,277 FinnGen participants. We identify 495 genome-trait associations in 56 genetic loci including 8 novel loci, with a considerable boost provided by the multivariate analysis. For 26 loci, fine-mapping identifies variants with a high causal probability, including 14 coding variants indicating likely causal genes. A phenome-wide analysis across 953 disease endpoints reveals disease associations for 40 lipid loci. For 11 coronary artery disease risk variants, we detect strong associations with lipid species. Our study demonstrates the power of multivariate genetic analysis in correlated lipidomics data and reveals genetic links between diseases and lipid species beyond the standard lipids.
    DOI:  https://doi.org/10.1038/s41467-023-42532-8
  4. Nat Commun. 2023 Nov 02. 14(1): 7016
    Striatum-projecting prefrontal cortex neurons support working memory maintenance.
    Maria Wilhelm, Yaroslav Sych, Aleksejs Fomins, José Luis Alatorre Warren, Christopher Lewis, Laia Serratosa Capdevila, Roman Boehringer, Elizabeth A Amadei, Benjamin Grewe, Eoin C O'Connor, Benjamin J Hall, Fritjof Helmchen.
      Neurons in the medial prefrontal cortex (mPFC) are functionally linked to working memory (WM) but how distinct projection pathways contribute to WM remains unclear. Based on optical recordings, optogenetic perturbations, and pharmacological interventions in male mice, we report here that dorsomedial striatum (dmStr)-projecting mPFC neurons are essential for WM maintenance, but not encoding or retrieval, in a T-maze spatial memory task. Fiber photometry of GCaMP6m-labeled mPFC→dmStr neurons revealed strongest activity during the maintenance period, and optogenetic inhibition of these neurons impaired performance only when applied during this period. Conversely, enhancing mPFC→dmStr pathway activity-via pharmacological suppression of HCN1 or by optogenetic activation during the maintenance period-alleviated WM impairment induced by NMDA receptor blockade. Moreover, cellular-resolution miniscope imaging revealed that >50% of mPFC→dmStr neurons are active during WM maintenance and that this subpopulation is distinct from neurons active during encoding and retrieval. In all task periods, neuronal sequences were evident. Striatum-projecting mPFC neurons thus critically contribute to spatial WM maintenance.
    DOI:  https://doi.org/10.1038/s41467-023-42777-3
  5. Nat Commun. 2023 Oct 30. 14(1): 6923
    Stress-induced red nucleus attenuation induces anxiety-like behavior and lymph node CCL5 secretion.
    Dong-Dong Shi, Ying-Dan Zhang, Sen Zhang, Bing-Bing Liao, Min-Yi Chu, Shanshan Su, Kaiming Zhuo, Hao Hu, Chen Zhang, Zhen Wang.
      Previous studies have speculated that brain activity directly controls immune responses in lymphoid organs. However, the upstream brain regions that control lymphoid organs and how they interface with lymphoid organs to produce stress-induced anxiety-like behavior remain elusive. Using stressed human participants and rat models, we show that CCL5 levels are increased in stressed individuals compared to controls. Stress-inducible CCL5 is mainly produced from cervical lymph nodes (CLN). Retrograde tracing from CLN identifies glutamatergic neurons in the red nucleus (RN), the activities of which are tightly correlated with CCL5 levels and anxiety-like behavior in male rats. Ablation or chemogenetic inhibition of RN glutamatergic neurons increases anxiety levels and CCL5 expression in the serum and CLNs, whereas pharmacogenetic activation of these neurons reduces anxiety levels and CCL5 synthesis after restraint stress exposure. Chemogenetic inhibition of the projection from primary motor cortex to RN elicits anxiety-like behavior and CCL5 synthesis. This brain-lymph node axis provides insights into lymph node tissue as a stress-responsive endocrine organ.
    DOI:  https://doi.org/10.1038/s41467-023-42814-1
  6. Nat Commun. 2023 Oct 28. 14(1): 6870
    XMAP: Cross-population fine-mapping by leveraging genetic diversity and accounting for confounding bias.
    Mingxuan Cai, Zhiwei Wang, Jiashun Xiao, Xianghong Hu, Gang Chen, Can Yang.
      Fine-mapping prioritizes risk variants identified by genome-wide association studies (GWASs), serving as a critical step to uncover biological mechanisms underlying complex traits. However, several major challenges still remain for existing fine-mapping methods. First, the strong linkage disequilibrium among variants can limit the statistical power and resolution of fine-mapping. Second, it is computationally expensive to simultaneously search for multiple causal variants. Third, the confounding bias hidden in GWAS summary statistics can produce spurious signals. To address these challenges, we develop a statistical method for cross-population fine-mapping (XMAP) by leveraging genetic diversity and accounting for confounding bias. By using cross-population GWAS summary statistics from global biobanks and genomic consortia, we show that XMAP can achieve greater statistical power, better control of false positive rate, and substantially higher computational efficiency for identifying multiple causal signals, compared to existing methods. Importantly, we show that the output of XMAP can be integrated with single-cell datasets, which greatly improves the interpretation of putative causal variants in their cellular context at single-cell resolution.
    DOI:  https://doi.org/10.1038/s41467-023-42614-7
  7. Nat Commun. 2023 Nov 02. 14(1): 7021
    Inhibition of glycolysis-driven immunosuppression with a nano-assembly enhances response to immune checkpoint blockade therapy in triple negative breast cancer.
    Xijiao Ren, Zhuo Cheng, Jinming He, Xuemei Yao, Yingqi Liu, Kaiyong Cai, Menghuan Li, Yan Hu, Zhong Luo.
      Immune-checkpoint inhibitors (ICI) are promising modalities for treating triple negative breast cancer (TNBC). However, hyperglycolysis, a hallmark of TNBC cells, may drive tumor-intrinsic PD-L1 glycosylation and boost regulatory T cell function to impair ICI efficacy. Herein, we report a tumor microenvironment-activatable nanoassembly based on self-assembled aptamer-polymer conjugates for the targeted delivery of glucose transporter 1 inhibitor BAY-876 (DNA-PAE@BAY-876), which remodels the immunosuppressive TME to enhance ICI response. Poly β-amino ester (PAE)-modified PD-L1 and CTLA-4-antagonizing aptamers (aptPD-L1 and aptCTLA-4) are synthesized and co-assembled into supramolecular nanoassemblies for carrying BAY-876. The acidic tumor microenvironment causes PAE protonation and triggers nanoassembly dissociation to initiate BAY-876 and aptamer release. BAY-876 selectively inhibits TNBC glycolysis to deprive uridine diphosphate N-acetylglucosamine and downregulate PD-L1 N-linked glycosylation, thus facilitating PD-L1 recognition of aptPD-L1 to boost anti-PD-L1 therapy. Meanwhile, BAY-876 treatment also elevates glucose supply to tumor-residing regulatory T cells (Tregs) for metabolically rewiring them into an immunostimulatory state, thus cooperating with aptCTLA-4-mediated immune-checkpoint inhibition to abolish Treg-mediated immunosuppression. DNA-PAE@BAY-876 effectively reprograms the immunosuppressive microenvironment in preclinical models of TNBC in female mice and provides a distinct approach for TNBC immunotherapy in the clinics.
    DOI:  https://doi.org/10.1038/s41467-023-42883-2
  8. Nat Commun. 2023 Oct 30. 14(1): 6928
    eQTL mapping in fetal-like pancreatic progenitor cells reveals early developmental insights into diabetes risk.
    iPSCORE Consortium
      The impact of genetic regulatory variation active in early pancreatic development on adult pancreatic disease and traits is not well understood. Here, we generate a panel of 107 fetal-like iPSC-derived pancreatic progenitor cells (iPSC-PPCs) from whole genome-sequenced individuals and identify 4065 genes and 4016 isoforms whose expression and/or alternative splicing are affected by regulatory variation. We integrate eQTLs identified in adult islets and whole pancreas samples, which reveal 1805 eQTL associations that are unique to the fetal-like iPSC-PPCs and 1043 eQTLs that exhibit regulatory plasticity across the fetal-like and adult pancreas tissues. Colocalization with GWAS risk loci for pancreatic diseases and traits show that some putative causal regulatory variants are active only in the fetal-like iPSC-PPCs and likely influence disease by modulating expression of disease-associated genes in early development, while others with regulatory plasticity likely exert their effects in both the fetal and adult pancreas by modulating expression of different disease genes in the two developmental stages.
    DOI:  https://doi.org/10.1038/s41467-023-42560-4
  9. Commun Biol. 2023 Nov 01. 6(1): 1108
    Cholesterol mediated ferroptosis suppression reveals essential roles of Coenzyme Q and squalene.
    Qi Sun, Diming Liu, Weiwei Cui, Huimin Cheng, Lixia Huang, Ruihao Zhang, Junlian Gu, Shuo Liu, Xiao Zhuang, Yi Lu, Bo Chu, Jian Li.
      Recent findings have shown that fatty acid metabolism is profoundly involved in ferroptosis. However, the role of cholesterol in this process remains incompletely understood. In this work, we show that modulating cholesterol levels changes vulnerability of cells to ferroptosis. Cholesterol alters metabolic flux of the mevalonate pathway by promoting Squalene Epoxidase (SQLE) degradation, a rate limiting step in cholesterol biosynthesis, thereby increasing both CoQ10 and squalene levels. Importantly, whereas inactivation of Farnesyl-Diphosphate Farnesyltransferase 1 (FDFT1), the branch point of cholesterol biosynthesis pathway, exhibits minimal effect on ferroptosis, simultaneous inhibition of both CoQ10 and squalene biosynthesis completely abrogates the effect of cholesterol. Mouse models of ischemia-reperfusion and doxorubicin induced hepatoxicity confirm the protective role of cholesterol in ferroptosis. Our study elucidates a potential role of ferroptosis in diseases related to dysregulation of cholesterol metabolism and suggests a possible therapeutic target that involves ferroptotic cell death.
    DOI:  https://doi.org/10.1038/s42003-023-05477-8
  10. Nat Genet. 2023 Nov 02.
    Phospholipid modifier PLAAT3 links defective PPARγ-dependent signaling to lipodystrophy.
      
    DOI:  https://doi.org/10.1038/s41588-023-01536-2
  11. Nature. 2023 Oct 31.
    Dengue is spreading in Europe: how worried should we be?
    Miryam Naddaf.
      
    Keywords:  Diseases; Epidemiology; Public health
    DOI:  https://doi.org/10.1038/d41586-023-03407-6
  12. Nature. 2023 Oct 30.
    Audio long read: Why BMI is flawed - and how to redefine obesity.
    McKenzie Prillaman, Benjamin Thompson.
      
    Keywords:  Health care; Obesity; Public health
    DOI:  https://doi.org/10.1038/d41586-023-03257-2
  13. Nat Commun. 2023 Nov 02. 14(1): 7003
    Structural basis for stabilisation of the RAD51 nucleoprotein filament by BRCA2.
    Robert Appleby, Luay Joudeh, Katie Cobbett, Luca Pellegrini.
      The BRCA2 tumour suppressor protein preserves genomic integrity via interactions with the DNA-strand exchange RAD51 protein in homology-directed repair. The RAD51-binding TR2 motif at the BRCA2 C-terminus is essential for protection and restart of stalled replication forks. Biochemical evidence shows that TR2 recognises filamentous RAD51, but existing models of TR2 binding to RAD51 lack a structural basis. Here we used cryo-electron microscopy and structure-guided mutagenesis to elucidate the mechanism of TR2 binding to nucleoprotein filaments of human RAD51. We find that TR2 binds across the protomer interface in the filament, acting as a brace for adjacent RAD51 molecules. TR2 targets an acidic-patch motif on human RAD51 that serves as a recruitment hub in fission yeast Rad51 for recombination mediators Rad52 and Rad55-Rad57. Our findings provide a structural rationale for RAD51 filament stabilisation by BRCA2 and reveal a common recruitment mechanism of recombination mediators to the RAD51 filament.
    DOI:  https://doi.org/10.1038/s41467-023-42830-1
  14. Nat Commun. 2023 Oct 30. 14(1): 6900
    DIAPH1-MFN2 interaction regulates mitochondria-SR/ER contact and modulates ischemic/hypoxic stress.
    Gautham Yepuri, Lisa M Ramirez, Gregory G Theophall, Sergei V Reverdatto, Nosirudeen Quadri, Syed Nurul Hasan, Lei Bu, Devi Thiagarajan, Robin Wilson, Raquel López Díez, Paul F Gugger, Kaamashri Mangar, Navneet Narula, Stuart D Katz, Boyan Zhou, Huilin Li, Aleksandr B Stotland, Roberta A Gottlieb, Ann Marie Schmidt, Alexander Shekhtman, Ravichandran Ramasamy.
      Inter-organelle contact and communication between mitochondria and sarco/endoplasmic reticulum (SR/ER) maintain cellular homeostasis and are profoundly disturbed during tissue ischemia. We tested the hypothesis that the formin Diaphanous-1 (DIAPH1), which regulates actin dynamics, signal transduction and metabolic functions, contributes to these processes. We demonstrate that DIAPH1 interacts directly with Mitofusin-2 (MFN2) to shorten mitochondria-SR/ER distance, thereby enhancing mitochondria-ER contact in cells including cardiomyocytes, endothelial cells and macrophages. Solution structure studies affirm the interaction between the Diaphanous Inhibitory Domain and the cytosolic GTPase domain of MFN2. In male rodent and human cardiomyocytes, DIAPH1-MFN2 interaction regulates mitochondrial turnover, mitophagy, and oxidative stress. Introduction of synthetic linker construct, which shorten the mitochondria-SR/ER distance, mitigated the molecular and functional benefits of DIAPH1 silencing in ischemia. This work establishes fundamental roles for DIAPH1-MFN2 interaction in the regulation of mitochondria-SR/ER contact networks. We propose that targeting pathways that regulate DIAPH1-MFN2 interactions may facilitate recovery from tissue ischemia.
    DOI:  https://doi.org/10.1038/s41467-023-42521-x
  15. Nat Commun. 2023 Nov 01. 14(1): 6770
    ARF1 prevents aberrant type I interferon induction by regulating STING activation and recycling.
    Maximilian Hirschenberger, Alice Lepelley, Ulrich Rupp, Susanne Klute, Victoria Hunszinger, Lennart Koepke, Veronika Merold, Blaise Didry-Barca, Fanny Wondany, Tim Bergner, Tatiana Moreau, Mathieu P Rodero, Reinhild Rösler, Sebastian Wiese, Stefano Volpi, Marco Gattorno, Riccardo Papa, Sally-Ann Lynch, Marte G Haug, Gunnar Houge, Kristen M Wigby, Jessica Sprague, Jerica Lenberg, Clarissa Read, Paul Walther, Jens Michaelis, Frank Kirchhoff, Carina C de Oliveira Mann, Yanick J Crow, Konstantin M J Sparrer.
      Type I interferon (IFN) signalling is tightly controlled. Upon recognition of DNA by cyclic GMP-AMP synthase (cGAS), stimulator of interferon genes (STING) translocates along the endoplasmic reticulum (ER)-Golgi axis to induce IFN signalling. Termination is achieved through autophagic degradation or recycling of STING by retrograde Golgi-to-ER transport. Here, we identify the GTPase ADP-ribosylation factor 1 (ARF1) as a crucial negative regulator of cGAS-STING signalling. Heterozygous ARF1 missense mutations cause a previously unrecognized type I interferonopathy associated with enhanced IFN-stimulated gene expression. Disease-associated, GTPase-defective ARF1 increases cGAS-STING dependent type I IFN signalling in cell lines and primary patient cells. Mechanistically, mutated ARF1 perturbs mitochondrial morphology, causing cGAS activation by aberrant mitochondrial DNA release, and leads to accumulation of active STING at the Golgi/ERGIC due to defective retrograde transport. Our data show an unexpected dual role of ARF1 in maintaining cGAS-STING homeostasis, through promotion of mitochondrial integrity and STING recycling.
    DOI:  https://doi.org/10.1038/s41467-023-42150-4
  16. Nat Commun. 2023 Nov 01. 14(1): 6982
    Hepatocyte FBXW7-dependent activity of nutrient-sensing nuclear receptors controls systemic energy homeostasis and NASH progression in male mice.
    Hui Xia, Catherine R Dufour, Younes Medkour, Charlotte Scholtes, Yonghong Chen, Christina Guluzian, Wafa B'chir, Vincent Giguère.
      Nonalcoholic steatohepatitis (NASH) is epidemiologically associated with obesity and diabetes and can lead to liver cirrhosis and hepatocellular carcinoma if left untreated. The intricate signaling pathways that orchestrate hepatocyte energy metabolism and cellular stress, intrahepatic cell crosstalk, as well as interplay between peripheral tissues remain elusive and are crucial for the development of anti-NASH therapies. Herein, we reveal E3 ligase FBXW7 as a key factor regulating hepatic catabolism, stress responses, systemic energy homeostasis, and NASH pathogenesis with attenuated FBXW7 expression as a feature of advanced NASH. Multiomics and pharmacological intervention showed that FBXW7 loss-of-function in hepatocytes disrupts a metabolic transcriptional axis conjointly controlled by the nutrient-sensing nuclear receptors ERRα and PPARα, resulting in suppression of fatty acid oxidation, elevated ER stress, apoptosis, immune infiltration, fibrogenesis, and ultimately NASH progression in male mice. These results provide the foundation for developing alternative strategies co-targeting ERRα and PPARα for the treatment of NASH.
    DOI:  https://doi.org/10.1038/s41467-023-42785-3
  17. Nat Commun. 2023 Nov 02. 14(1): 7030
    A neurodegeneration checkpoint mediated by REST protects against the onset of Alzheimer's disease.
    Liviu Aron, Chenxi Qiu, Zhen Kai Ngian, Marianna Liang, Derek Drake, Jaejoon Choi, Marty A Fernandez, Perle Roche, Emma L Bunting, Ella K Lacey, Sara E Hamplova, Monlan Yuan, Michael S Wolfe, David A Bennett, Eunjung A Lee, Bruce A Yankner.
      Many aging individuals accumulate the pathology of Alzheimer's disease (AD) without evidence of cognitive decline. Here we describe an integrated neurodegeneration checkpoint response to early pathological changes that restricts further disease progression and preserves cognitive function. Checkpoint activation is mediated by the REST transcriptional repressor, which is induced in cognitively-intact aging humans and AD mouse models at the onset of amyloid β-protein (Aβ) deposition and tau accumulation. REST induction is mediated by the unfolded protein response together with β-catenin signaling. A consequence of this response is the targeting of REST to genes involved in key pathogenic pathways, resulting in downregulation of gamma secretase, tau kinases, and pro-apoptotic proteins. Deletion of REST in the 3xTg and J20 AD mouse models accelerates Aβ deposition and the accumulation of misfolded and phosphorylated tau, leading to neurodegeneration and cognitive decline. Conversely, viral-mediated overexpression of REST in the hippocampus suppresses Aβ and tau pathology. Thus, REST mediates a neurodegeneration checkpoint response with multiple molecular targets that may protect against the onset of AD.
    DOI:  https://doi.org/10.1038/s41467-023-42704-6
  18. Nat Commun. 2023 Oct 31. 14(1): 6963
    Self-promoted electroactive biomimetic mineralized scaffolds for bacteria-infected bone regeneration.
    Zixin Li, Danqing He, Bowen Guo, Zekun Wang, Huajie Yu, Yu Wang, Shanshan Jin, Min Yu, Lisha Zhu, Liyuan Chen, Chengye Ding, Xiaolan Wu, Tianhao Wu, Shiqiang Gong, Jing Mao, Yanheng Zhou, Dan Luo, Yan Liu.
      Infected bone defects are a major challenge in orthopedic treatment. Native bone tissue possesses an endogenous electroactive interface that induces stem cell differentiation and inhibits bacterial adhesion and activity. However, traditional bone substitutes have difficulty in reconstructing the electrical environment of bone. In this study, we develop a self-promoted electroactive mineralized scaffold (sp-EMS) that generates weak currents via spontaneous electrochemical reactions to activate voltage-gated Ca2+ channels, enhance adenosine triphosphate-induced actin remodeling, and ultimately achieve osteogenic differentiation of mesenchymal stem cells by activating the BMP2/Smad5 pathway. Furthermore, we show that the electroactive interface provided by the sp-EMS inhibits bacterial adhesion and activity via electrochemical products and concomitantly generated reactive oxygen species. We find that the osteogenic and antibacterial dual functions of the sp-EMS depend on its self-promoting electrical stimulation. We demonstrate that in vivo, the sp-EMS achieves complete or nearly complete in situ infected bone healing, from a rat calvarial defect model with single bacterial infection, to a rabbit open alveolar bone defect model and a beagle dog vertical bone defect model with the complex oral bacterial microenvironment. This translational study demonstrates that the electroactive bone graft presents a promising therapeutic platform for complex defect repair.
    DOI:  https://doi.org/10.1038/s41467-023-42598-4
  19. Nat Commun. 2023 Oct 30. 14(1): 6911
    Microglia-mediated demyelination protects against CD8+ T cell-driven axon degeneration in mice carrying PLP defects.
    Janos Groh, Tassnim Abdelwahab, Yogita Kattimani, Michaela Hörner, Silke Loserth, Viktoria Gudi, Robert Adalbert, Fabian Imdahl, Antoine-Emmanuel Saliba, Michael Coleman, Martin Stangel, Mikael Simons, Rudolf Martini.
      Axon degeneration and functional decline in myelin diseases are often attributed to loss of myelin but their relation is not fully understood. Perturbed myelinating glia can instigate chronic neuroinflammation and contribute to demyelination and axonal damage. Here we study mice with distinct defects in the proteolipid protein 1 gene that develop axonal damage which is driven by cytotoxic T cells targeting myelinating oligodendrocytes. We show that persistent ensheathment with perturbed myelin poses a risk for axon degeneration, neuron loss, and behavioral decline. We demonstrate that CD8+ T cell-driven axonal damage is less likely to progress towards degeneration when axons are efficiently demyelinated by activated microglia. Mechanistically, we show that cytotoxic T cell effector molecules induce cytoskeletal alterations within myelinating glia and aberrant actomyosin constriction of axons at paranodal domains. Our study identifies detrimental axon-glia-immune interactions which promote neurodegeneration and possible therapeutic targets for disorders associated with myelin defects and neuroinflammation.
    DOI:  https://doi.org/10.1038/s41467-023-42570-2
  20. Nat Commun. 2023 10 28. 14(1): 6883
    A phosphoinositide switch mediates exocyst recruitment to multivesicular endosomes for exosome secretion.
    Di-Ao Liu, Kai Tao, Bin Wu, Ziyan Yu, Malwina Szczepaniak, Matthew Rames, Changsong Yang, Tatyana Svitkina, Yueyao Zhu, Fengyuan Xu, Xiaolin Nan, Wei Guo.
      Exosomes are secreted to the extracellular milieu when multivesicular endosomes (MVEs) dock and fuse with the plasma membrane. However, MVEs are also known to fuse with lysosomes for degradation. How MVEs are directed to the plasma membrane for exosome secretion rather than to lysosomes is unclear. Here we report that a conversion of phosphatidylinositol-3-phosphate (PI(3)P) to phosphatidylinositol-4-phosphate (PI(4)P) catalyzed sequentially by Myotubularin 1 (MTM1) and phosphatidylinositol 4-kinase type IIα (PI4KIIα) on the surface of MVEs mediates the recruitment of the exocyst complex. The exocyst then targets the MVEs to the plasma membrane for exosome secretion. We further demonstrate that disrupting PI(4)P generation or exocyst function blocked exosomal secretion of Programmed death-ligand 1 (PD-L1), a key immune checkpoint protein in tumor cells, and led to its accumulation in lysosomes. Together, our study suggests that the PI(3)P to PI(4)P conversion on MVEs and the recruitment of the exocyst direct the exocytic trafficking of MVEs for exosome secretion.
    DOI:  https://doi.org/10.1038/s41467-023-42661-0
  21. Sci Immunol. 2023 Nov 03. 8(89): eadi5377
    Regulatory T cells shield muscle mitochondria from interferon-γ-mediated damage to promote the beneficial effects of exercise.
    P Kent Langston, Yizhi Sun, Birgitta A Ryback, Amber L Mueller, Bruce M Spiegelman, Christophe Benoist, Diane Mathis.
      Exercise enhances physical performance and reduces the risk of many disorders such as cardiovascular disease, type 2 diabetes, dementia, and cancer. Exercise characteristically incites an inflammatory response, notably in skeletal muscles. Although some effector mechanisms have been identified, regulatory elements activated in response to exercise remain obscure. Here, we have addressed the roles of Foxp3+CD4+ regulatory T cells (Tregs) in the healthful activities of exercise via immunologic, transcriptomic, histologic, metabolic, and biochemical analyses of acute and chronic exercise models in mice. Exercise rapidly induced expansion of the muscle Treg compartment, thereby guarding against overexuberant production of interferon-γ and consequent metabolic disruptions, particularly mitochondrial aberrancies. The performance-enhancing effects of exercise training were dampened in the absence of Tregs. Thus, exercise is a natural Treg booster with therapeutic potential in disease and aging contexts.
    DOI:  https://doi.org/10.1126/sciimmunol.adi5377
  22. Nat Genet. 2023 Oct 30.
    A pan-tissue survey of mosaic chromosomal alterations in 948 individuals.
    Teng Gao, Maria Eleni Kastriti, Viktor Ljungström, Andreas Heinzel, Arthur S Tischler, Rainer Oberbauer, Po-Ru Loh, Igor Adameyko, Peter J Park, Peter V Kharchenko.
      Genetic mutations accumulate in an organism's body throughout its lifetime. While somatic single-nucleotide variants have been well characterized in the human body, the patterns and consequences of large chromosomal alterations in normal tissues remain largely unknown. Here, we present a pan-tissue survey of mosaic chromosomal alterations (mCAs) in 948 healthy individuals from the Genotype-Tissue Expression project, augmenting RNA-based allelic imbalance estimation with haplotype phasing. We found that approximately a quarter of the individuals carry a clonally-expanded mCA in at least one tissue, with incidence strongly correlated with age. The prevalence and genome-wide patterns of mCAs vary considerably across tissue types, suggesting tissue-specific mutagenic exposure and selection pressures. The mCA landscapes in normal adrenal and pituitary glands resemble those in tumors arising from these tissues, whereas the same is not true for the esophagus and skin. Together, our findings show a widespread age-dependent emergence of mCAs across normal human tissues with intricate connections to tumorigenesis.
    DOI:  https://doi.org/10.1038/s41588-023-01537-1
  23. Nat Commun. 2023 Oct 31. 14(1): 6941
    Antigen presentation by B cells enables epitope spreading across an MHC barrier.
    Cecilia Fahlquist-Hagert, Thomas R Wittenborn, Ewa Terczyńska-Dyla, Kristian Savstrup Kastberg, Emily Yang, Alysa Nicole Rallistan, Quinton Raymond Markett, Gudrun Winther, Sofie Fonager, Lasse F Voss, Mathias K Pedersen, Nina van Campen, Alexey Ferapontov, Lisbeth Jensen, Jinrong Huang, John D Nieland, Cees E van der Poel, Johan Palmfeldt, Michael C Carroll, Paul J Utz, Yonglun Luo, Lin Lin, Søren E Degn.
      Circumstantial evidence suggests that B cells may instruct T cells to break tolerance. Here, to test this hypothesis, we used a murine model in which a single B cell clone precipitates an autoreactive response resembling systemic lupus erythematosus (SLE). The initiating clone did not need to enter germinal centers to precipitate epitope spreading. Rather, it localized to extrafollicular splenic bridging channels early in the response. Autoantibody produced by the initiating clone was not sufficient to drive the autoreactive response. Subsequent epitope spreading depended on antigen presentation and was compartmentalized by major histocompatibility complex (MHC). B cells carrying two MHC haplotypes could bridge the MHC barrier between B cells that did not share MHC. Thus, B cells directly relay autoreactivity between two separate compartments of MHC-restricted T cells, leading to inclusion of distinct B cell populations in germinal centers. Our findings demonstrate that B cells initiate and propagate the autoimmune response.
    DOI:  https://doi.org/10.1038/s41467-023-42541-7
  24. Nat Commun. 2023 Nov 02. 14(1): 7002
    Deep brain stimulation of thalamic nucleus reuniens promotes neuronal and cognitive resilience in an Alzheimer's disease mouse model.
    Shiri Shoob, Nadav Buchbinder, Ortal Shinikamin, Or Gold, Halit Baeloha, Tomer Langberg, Daniel Zarhin, Ilana Shapira, Gabriella Braun, Naomi Habib, Inna Slutsky.
      The mechanisms that confer cognitive resilience to Alzheimer's Disease (AD) are not fully understood. Here, we describe a neural circuit mechanism underlying this resilience in a familial AD mouse model. In the prodromal disease stage, interictal epileptiform spikes (IESs) emerge during anesthesia in the CA1 and mPFC regions, leading to working memory disruptions. These IESs are driven by inputs from the thalamic nucleus reuniens (nRE). Indeed, tonic deep brain stimulation of the nRE (tDBS-nRE) effectively suppresses IESs and restores firing rate homeostasis under anesthesia, preventing further impairments in nRE-CA1 synaptic facilitation and working memory. Notably, applying tDBS-nRE during the prodromal phase in young APP/PS1 mice mitigates age-dependent memory decline. The IES rate during anesthesia in young APP/PS1 mice correlates with later working memory impairments. These findings highlight the nRE as a central hub of functional resilience and underscore the clinical promise of DBS in conferring resilience to AD pathology by restoring circuit-level homeostasis.
    DOI:  https://doi.org/10.1038/s41467-023-42721-5
  25. Sci Adv. 2023 11 03. 9(44): eadh2584
    UNC-49 is a redox-sensitive GABAA receptor that regulates the mitochondrial unfolded protein response cell nonautonomously.
    Franziska Pohl, Allison L Germann, Jack Mao, Sydney Hou, Bayode Bakare, Paul Kong Thoo Lin, Kyari Yates, Michael L Nonet, Gustav Akk, Kerry Kornfeld, Jason M Held.
      The γ-aminobutyric acid-mediated (GABAergic) system participates in many aspects of organismal physiology and disease, including proteostasis, neuronal dysfunction, and life-span extension. Many of these phenotypes are also regulated by reactive oxygen species (ROS), but the redox mechanisms linking the GABAergic system to these phenotypes are not well defined. Here, we report that GABAergic redox signaling cell nonautonomously activates many stress response pathways in Caenorhabditis elegans and enhances vulnerability to proteostasis disease in the absence of oxidative stress. Cell nonautonomous redox activation of the mitochondrial unfolded protein response (mitoUPR) proteostasis network requires UNC-49, a GABAA receptor that we show is activated by hydrogen peroxide. MitoUPR induction by a spinocerebellar ataxia type 3 (SCA3) C. elegans neurodegenerative disease model was similarly dependent on UNC-49 in C. elegans. These results demonstrate a multi-tissue paradigm for redox signaling in the GABAergic system that is transduced via a GABAA receptor to function in cell nonautonomous regulation of health, proteostasis, and disease.
    DOI:  https://doi.org/10.1126/sciadv.adh2584
  26. Nat Commun. 2023 Oct 30. 14(1): 6908
    Farnesoid X receptor activation by bile acids suppresses lipid peroxidation and ferroptosis.
    Juliane Tschuck, Lea Theilacker, Ina Rothenaigner, Stefanie A I Weiß, Banu Akdogan, Van Thanh Lam, Constanze Müller, Roman Graf, Stefanie Brandner, Christian Pütz, Tamara Rieder, Philippe Schmitt-Kopplin, Michelle Vincendeau, Hans Zischka, Kenji Schorpp, Kamyar Hadian.
      Ferroptosis is a regulated cell death modality that occurs upon iron-dependent lipid peroxidation. Recent research has identified many regulators that induce or inhibit ferroptosis; yet, many regulatory processes and networks remain to be elucidated. In this study, we performed a chemical genetics screen using small molecules with known mode of action and identified two agonists of the nuclear receptor Farnesoid X Receptor (FXR) that suppress ferroptosis, but not apoptosis or necroptosis. We demonstrate that in liver cells with high FXR levels, knockout or inhibition of FXR sensitized cells to ferroptotic cell death, whereas activation of FXR by bile acids inhibited ferroptosis. Furthermore, FXR inhibited ferroptosis in ex vivo mouse hepatocytes and human hepatocytes differentiated from induced pluripotent stem cells. Activation of FXR significantly reduced lipid peroxidation by upregulating the ferroptosis gatekeepers GPX4, FSP1, PPARα, SCD1, and ACSL3. Together, we report that FXR coordinates the expression of ferroptosis-inhibitory regulators to reduce lipid peroxidation, thereby acting as a guardian of ferroptosis.
    DOI:  https://doi.org/10.1038/s41467-023-42702-8
  27. J Clin Invest. 2023 Nov 01. pii: e170072. [Epub ahead of print]133(21):
    A PPARγ/long noncoding RNA axis regulates adipose thermoneutral remodeling in mice.
    Zhengyi Zhang, Ya Cui, Vivien Su, Dan Wang, Marcus J Tol, Lijing Cheng, Xiaohui Wu, Jason Kim, Prashant Rajbhandari, Sicheng Zhang, Wei Li, Peter Tontonoz, Claudio J Villanueva, Tamer Sallam.
      Interplay between energy-storing white adipose cells and thermogenic beige adipocytes contributes to obesity and insulin resistance. Irrespective of specialized niche, adipocytes require the activity of the nuclear receptor PPARγ for proper function. Exposure to cold or adrenergic signaling enriches thermogenic cells though multiple pathways that act synergistically with PPARγ; however, the molecular mechanisms by which PPARγ licenses white adipose tissue to preferentially adopt a thermogenic or white adipose fate in response to dietary cues or thermoneutral conditions are not fully elucidated. Here, we show that a PPARγ/long noncoding RNA (lncRNA) axis integrates canonical and noncanonical thermogenesis to restrain white adipose tissue heat dissipation during thermoneutrality and diet-induced obesity. Pharmacologic inhibition or genetic deletion of the lncRNA Lexis enhances uncoupling protein 1-dependent (UCP1-dependent) and -independent thermogenesis. Adipose-specific deletion of Lexis counteracted diet-induced obesity, improved insulin sensitivity, and enhanced energy expenditure. Single-nuclei transcriptomics revealed that Lexis regulates a distinct population of thermogenic adipocytes. We systematically map Lexis motif preferences and show that it regulates the thermogenic program through the activity of the metabolic GWAS gene and WNT modulator TCF7L2. Collectively, our studies uncover a new mode of crosstalk between PPARγ and WNT that preserves white adipose tissue plasticity.
    Keywords:  Adipose tissue; Cardiology; Metabolism; Molecular genetics; Noncoding RNAs
    DOI:  https://doi.org/10.1172/JCI170072
  28. Nat Commun. 2023 Oct 28. 14(1): 6875
    Lateral hypothalamic proenkephalin neurons drive threat-induced overeating associated with a negative emotional state.
    In-Jee You, Yeeun Bae, Alec R Beck, Sora Shin.
      Psychological stressors, like the nearby presence of a predator, can be strong enough to induce physiological/hormonal alterations, leading to appetite changes. However, little is known about how threats can alter feeding-related hypothalamic circuit functions. Here, we found that proenkephalin (Penk)-expressing lateral hypothalamic (LHPenk) neurons of mice exposed to predator scent stimulus (PSS) show sensitized responses to high-fat diet (HFD) eating, whereas silencing of the same neurons normalizes PSS-induced HFD overconsumption associated with a negative emotional state. Downregulation of endogenous enkephalin peptides in the LH is crucial for inhibiting the neuronal and behavioral changes developed after PSS exposure. Furthermore, elevated corticosterone after PSS contributes to enhance the reactivity of glucocorticoid receptor (GR)-containing LHPenk neurons to HFD, whereas pharmacological inhibition of GR in the LH suppresses PSS-induced maladaptive behavioral responses. We have thus identified the LHPenk neurons as a critical component in the threat-induced neuronal adaptation that leads to emotional overconsumption.
    DOI:  https://doi.org/10.1038/s41467-023-42623-6
  29. Nature. 2023 Nov 01.
    Glioma synapses recruit mechanisms of adaptive plasticity.
    Kathryn R Taylor, Tara Barron, Alexa Hui, Avishay Spitzer, Belgin Yalçin, Alexis E Ivec, Anna C Geraghty, Griffin G Hartmann, Marlene Arzt, Shawn M Gillespie, Yoon Seok Kim, Samin Maleki Jahan, Helena Zhang, Kiarash Shamardani, Minhui Su, Lijun Ni, Peter P Du, Pamelyn J Woo, Arianna Silva-Torres, Humsa S Venkatesh, Rebecca Mancusi, Anitha Ponnuswami, Sara Mulinyawe, Michael B Keough, Isabelle Chau, Razina Aziz-Bose, Itay Tirosh, Mario L Suvà, Michelle Monje.
      The role of the nervous system in the regulation of cancer is increasingly appreciated. In gliomas, neuronal activity drives tumour progression through paracrine signalling factors such as neuroligin-3 and brain-derived neurotrophic factor1-3 (BDNF), and also through electrophysiologically functional neuron-to-glioma synapses mediated by AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptors4,5. The consequent glioma cell membrane depolarization drives tumour proliferation4,6. In the healthy brain, activity-regulated secretion of BDNF promotes adaptive plasticity of synaptic connectivity7,8 and strength9-15. Here we show that malignant synapses exhibit similar plasticity regulated by BDNF. Signalling through the receptor tropomyosin-related kinase B16 (TrkB) to CAMKII, BDNF promotes AMPA receptor trafficking to the glioma cell membrane, resulting in increased amplitude of glutamate-evoked currents in the malignant cells. Linking plasticity of glioma synaptic strength to tumour growth, graded optogenetic control of glioma membrane potential demonstrates that greater depolarizing current amplitude promotes increased glioma proliferation. This potentiation of malignant synaptic strength shares mechanistic features with synaptic plasticity17-22 that contributes to memory and learning in the healthy brain23-26. BDNF-TrkB signalling also regulates the number of neuron-to-glioma synapses. Abrogation of activity-regulated BDNF secretion from the brain microenvironment or loss of glioma TrkB expression robustly inhibits tumour progression. Blocking TrkB genetically or pharmacologically abrogates these effects of BDNF on glioma synapses and substantially prolongs survival in xenograft models of paediatric glioblastoma and diffuse intrinsic pontine glioma. Together, these findings indicate that BDNF-TrkB signalling promotes malignant synaptic plasticity and augments tumour progression.
    DOI:  https://doi.org/10.1038/s41586-023-06678-1
  30. Nat Immunol. 2023 Nov 01.
    Divergent mechanisms of inflammasome activation in neutrophil early response and inflammation.
    Sergio D Catz.
      
    DOI:  https://doi.org/10.1038/s41590-023-01684-x
  31. Nat Neurosci. 2023 Nov 02.
    Age-related dysregulation of homeostatic control in neuronal microcircuits.
    Carola I Radulescu, Nazanin Doostdar, Nawal Zabouri, Leire Melgosa-Ecenarro, Xingjian Wang, Sadra Sadeh, Pavlina Pavlidi, Joe Airey, Maksym Kopanitsa, Claudia Clopath, Samuel J Barnes.
      Neuronal homeostasis prevents hyperactivity and hypoactivity. Age-related hyperactivity suggests homeostasis may be dysregulated in later life. However, plasticity mechanisms preventing age-related hyperactivity and their efficacy in later life are unclear. We identify the adult cortical plasticity response to elevated activity driven by sensory overstimulation, then test how plasticity changes with age. We use in vivo two-photon imaging of calcium-mediated cellular/synaptic activity, electrophysiology and c-Fos-activity tagging to show control of neuronal activity is dysregulated in the visual cortex in late adulthood. Specifically, in young adult cortex, mGluR5-dependent population-wide excitatory synaptic weakening and inhibitory synaptogenesis reduce cortical activity following overstimulation. In later life, these mechanisms are downregulated, so that overstimulation results in synaptic strengthening and elevated activity. We also find overstimulation disrupts cognition in older but not younger animals. We propose that specific plasticity mechanisms fail in later life dysregulating neuronal microcircuit homeostasis and that the age-related response to overstimulation can impact cognitive performance.
    DOI:  https://doi.org/10.1038/s41593-023-01451-z
  32. Nat Rev Genet. 2023 Nov 01.
    A genetic atlas of the human blood proteome.
    Michael Attwaters.
      
    DOI:  https://doi.org/10.1038/s41576-023-00673-y
  33. Nat Commun. 2023 Oct 31. 14(1): 6953
    An in situ dual-anchoring strategy for enhanced immobilization of PD-L1 to treat autoimmune diseases.
    Shenqiang Wang, Ying Zhang, Yanfang Wang, Yinxian Yang, Sheng Zhao, Tao Sheng, Yuqi Zhang, Zhen Gu, Jinqiang Wang, Jicheng Yu.
      Immune checkpoints play key roles in maintaining self-tolerance. Targeted potentiation of the checkpoint molecule PD-L1 through in situ manipulation offers clinical promise for patients with autoimmune diseases. However, the therapeutic effects of these approaches are often compromised by limited specificity and inadequate expression. Here, we report a two-step dual-anchor coupling strategy for enhanced immobilization of PD-L1 on target endogenous cells by integrating bioorthogonal chemistry and physical insertion of the cell membrane. In both type 1 diabetes and rheumatoid arthritis mouse models, we demonstrate that this approach leads to elevated and sustained conjugation of PD-L1 on target cells, resulting in significant suppression of autoreactive immune cell activation, recruitment of regulatory T cells, and systematic reshaping of the immune environment. Furthermore, it restores glucose homeostasis in type 1 diabetic mice for over 100 days. This specific in situ bioengineering approach potentiates the functions of PD-L1 and represents its translational potential.
    DOI:  https://doi.org/10.1038/s41467-023-42725-1
  34. Nat Commun. 2023 10 28. 14(1): 6887
    Ventral striatal islands of Calleja neurons bidirectionally mediate depression-like behaviors in mice.
    Yun-Feng Zhang, Jialiang Wu, Yingqi Wang, Natalie L Johnson, Janardhan P Bhattarai, Guanqing Li, Wenqiang Wang, Camilo Guevara, Hannah Shoenhard, Marc V Fuccillo, Daniel W Wesson, Minghong Ma.
      The ventral striatum is a reward center implicated in the pathophysiology of depression. It contains islands of Calleja, clusters of dopamine D3 receptor-expressing granule cells, predominantly in the olfactory tubercle (OT). These OT D3 neurons regulate self-grooming, a repetitive behavior manifested in affective disorders. Here we show that chronic restraint stress (CRS) induces robust depression-like behaviors in mice and decreases excitability of OT D3 neurons. Ablation or inhibition of these neurons leads to depression-like behaviors, whereas their activation ameliorates CRS-induced depression-like behaviors. Moreover, activation of OT D3 neurons has a rewarding effect, which diminishes when grooming is blocked. Finally, we propose a model that explains how OT D3 neurons may influence dopamine release via synaptic connections with OT spiny projection neurons (SPNs) that project to midbrain dopamine neurons. Our study reveals a crucial role of OT D3 neurons in bidirectionally mediating depression-like behaviors, suggesting a potential therapeutic target.
    DOI:  https://doi.org/10.1038/s41467-023-42662-z
  35. Science. 2023 Nov 03. 382(6670): 534-541
    CD8 T cell tolerance results from eviction of immature autoreactive cells from the thymus.
    Mohamed Elsherif Badr, Zhongmei Zhang, Xuguang Tai, Alfred Singer.
      CD8 T cell tolerance is thought to result from clonal deletion of autoreactive thymocytes before they differentiate into mature CD8 T cells in the thymus. However, we report that, in mice, CD8 T cell tolerance instead results from premature thymic eviction of immature autoreactive CD8 thymocytes into the periphery, where they differentiate into self-tolerant mature CD8 T cells. Premature thymic eviction is triggered by T cell receptor (TCR)-driven down-regulation of the transcriptional repressor Gfi1, which induces expression of sphingosine-1-phosphate receptor-1 (S1P1) on negatively selected immature CD8 thymocytes. Thus, premature thymic eviction is the basis for CD8 T cell tolerance and is the mechanism responsible for the appearance in the periphery of mature CD8 T cells bearing autoreactive TCRs that are absent from the thymus.
    DOI:  https://doi.org/10.1126/science.adh4124
  36. J Cell Sci. 2023 Nov 03. pii: jcs.261402. [Epub ahead of print]
    Cholesterol regulates insulin-induced mTORC1 signaling.
    Kolaparamba V Navyasree, Shikha T Ramesh, Perunthottathu K Umasankar.
      The rapid activation of the critical kinase, mechanistic target of rapamycin complex-1 (mTORC1) by insulin is key to cell growth in mammals, but the regulatory factors remain unclear. Here, we demonstrate that cholesterol plays a crucial role in the regulation of insulin-stimulated mTORC1 signaling. The rapid progression of insulin-induced mTORC1 signaling declines in sterol-depleted cells and restores in cholesterol-repleted cells. In insulin-stimulated cells, cholesterol promotes recruitment of mTORC1 onto lysosomes without affecting insulin-induced dissociation of the TSC complex from lysosomes, thereby enabling complete activation of mTORC1. We also show that under prolonged starvation conditions, cholesterol coordinates with autophagy to support mTORC1 reactivation on lysosomes thereby restoring insulin-responsive mTORC1 signaling. Further, we identify that Smith-Lemli-Opitz Syndrome (SLOS) patient fibroblasts and HeLa-SLOS model which are deficient in cholesterol biosynthesis exhibit defects in insulin-mTORC1 growth axis. These defects are rescued by supplementation of exogenous cholesterol or by expression of constitutively active Rag GTPase, a downstream activator of mTORC1. Overall, our findings propose novel signal integration mechanisms to achieve spatial and temporal control of mTORC1-dependent growth signaling and their aberrations in disease.
    Keywords:  Cholesterol; Insulin; Lysosome; Signaling; mTORC1
    DOI:  https://doi.org/10.1242/jcs.261402
  37. Sci Adv. 2023 Nov 03. 9(44): eadh9603
    4E-BP1-dependent translation in nociceptors controls mechanical hypersensitivity via TRIM32/type I interferon signaling.
    Calvin Wong, Diana Tavares-Ferreira, Carolina Thörn Perez, Behrang Sharif, Sonali Uttam, Mehdi Amiri, Kevin C Lister, Mehdi Hooshmandi, Vivienne Nguyen, Philippe Séguéla, Nahum Sonenberg, Theodore J Price, Christos G Gkogkas, Arkady Khoutorsky.
      Activation of the mechanistic target of rapamycin complex 1 (mTORC1) contributes to the development of chronic pain. However, the specific mechanisms by which mTORC1 causes hypersensitivity remain elusive. The eukaryotic initiation factor 4E-binding protein 1 (4E-BP1) is a key mTORC1 downstream effector that represses translation initiation. Here, we show that nociceptor-specific deletion of 4E-BP1, mimicking activation of mTORC1-dependent translation, is sufficient to cause mechanical hypersensitivity. Using translating ribosome affinity purification in nociceptors lacking 4E-BP1, we identified a pronounced translational up-regulation of tripartite motif-containing protein 32 (TRIM32), an E3 ubiquitin ligase that promotes interferon signaling. Down-regulation of TRIM32 in nociceptors or blocking type I interferon signaling reversed the mechanical hypersensitivity in mice lacking 4E-BP1. Furthermore, nociceptor-specific ablation of TRIM32 alleviated mechanical hypersensitivity caused by tissue inflammation. These results show that mTORC1 in nociceptors promotes hypersensitivity via 4E-BP1-dependent up-regulation of TRIM32/interferon signaling and identify TRIM32 as a therapeutic target in inflammatory pain.
    DOI:  https://doi.org/10.1126/sciadv.adh9603
  38. Nat Commun. 2023 Nov 01. 14(1): 6991
    Follicle-stimulating hormone orchestrates glucose-stimulated insulin secretion of pancreatic islets.
    Yi Cheng, Hong Zhu, Jun Ren, Hai-Yan Wu, Jia-En Yu, Lu-Yang Jin, Hai-Yan Pang, Hai-Tao Pan, Si-Si Luo, Jing Yan, Kai-Xuan Dong, Long-Yun Ye, Cheng-Liang Zhou, Jie-Xue Pan, Zhuo-Xian Meng, Ting Yu, Li Jin, Xian-Hua Lin, Yan-Ting Wu, Hong-Bo Yang, Xin-Mei Liu, Jian-Zhong Sheng, Guo-Lian Ding, He-Feng Huang.
      Follicle-stimulating hormone (FSH) is involved in mammalian reproduction via binding to FSH receptor (FSHR). However, several studies have found that FSH and FSHR play important roles in extragonadal tissue. Here, we identified the expression of FSHR in human and mouse pancreatic islet β-cells. Blocking FSH signaling by Fshr knock-out led to impaired glucose tolerance owing to decreased insulin secretion, while high FSH levels caused insufficient insulin secretion as well. In vitro, we found that FSH orchestrated glucose-stimulated insulin secretion (GSIS) in a bell curve manner. Mechanistically, FSH primarily activates Gαs via FSHR, promoting the cAMP/protein kinase A (PKA) and calcium pathways to stimulate GSIS, whereas high FSH levels could activate Gαi to inhibit the cAMP/PKA pathway and the amplified effect on GSIS. Our results reveal the role of FSH in regulating pancreatic islet insulin secretion and provide avenues for future clinical investigation and therapeutic strategies for postmenopausal diabetes.
    DOI:  https://doi.org/10.1038/s41467-023-42801-6
  39. Nat Commun. 2023 Oct 30. 14(1): 6920
    Self-reported childhood family adversity is linked to an attenuated gain of trust during adolescence.
    NSPN Consortium
      A longstanding proposal in developmental research is that childhood family experiences provide a template that shapes a capacity for trust-based social relationships. We leveraged longitudinal data from a cohort of healthy adolescents (n = 570, aged 14-25), which included decision-making and psychometric data, to characterise normative developmental trajectories of trust behaviour and inter-individual differences therein. Extending on previous cross-sectional findings from the same cohort, we show that a task-based measure of trust increases longitudinally from adolescence into young adulthood. Computational modelling suggests this is due to a decrease in social risk aversion. Self-reported family adversity attenuates this developmental gain in trust behaviour, and within our computational model, this relates to a higher 'irritability' parameter in those reporting greater adversity. Unconditional trust at measurement time point T1 predicts the longitudinal trajectory of self-reported peer relation quality, particularly so for those with higher family adversity, consistent with trust acting as a resilience factor.
    DOI:  https://doi.org/10.1038/s41467-023-41531-z
  40. Nat Biomed Eng. 2023 Nov 02.
    Glycation-driven matrix crosslinking in cirrhosis.
    Orit Kollet, Irit Sagi.
      
    DOI:  https://doi.org/10.1038/s41551-023-01119-w
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