bims-nimamd Biomed News
on Neuroimmunity and neuroinflammation in ageing and metabolic disease
Issue of 2024–02–11
forty-one papers selected by
Fawaz Alzaïd, Sorbonne Université
  1. The gift of feedback.
  2. The genetic basis of autoimmunity seen through the lens of T cell functional traits.
  3. Artesunate treats obesity in male mice and non-human primates through GDF15/GFRAL signalling axis.
  4. Protection against overfeeding-induced weight gain is preserved in obesity but does not require FGF21 or MC4R.
  5. Epithelial zonation along the mouse and human small intestine defines five discrete metabolic domains.
  6. Identification of myeloid-derived growth factor as a mechanically-induced, growth-promoting angiocrine signal for human hepatocytes.
  7. mtDNA caught in the act again.
  8. Glucocorticoids increase adiposity by stimulating Krüppel-like factor 9 expression in macrophages.
  9. Pathogenic NLRP3 mutants form constitutively active inflammasomes resulting in immune-metabolic limitation of IL-1β production.
  10. Convergence of coronary artery disease genes onto endothelial cell programs.
  11. Bystander activated CD8+ T cells mediate neuropathology during viral infection via antigen-independent cytotoxicity.
  12. T-bet+ B cells are activated by and control endogenous retroviruses through TLR-dependent mechanisms.
  13. The liver and muscle secreted HFE2-protein maintains central nervous system blood vessel integrity.
  14. B cell-reactive triad of B cells, follicular helper and regulatory T cells at homeostasis.
  15. Relaxation of mitochondrial hyperfusion in the diabetic retina via N6-furfuryladenosine confers neuroprotection regardless of glycaemic status.
  16. DNA hypomethylation ameliorates erosive inflammatory arthritis by modulating interferon regulatory factor-8.
  17. Time for growth.
  18. 5-aminosalicylic acid suppresses osteoarthritis through the OSCAR-PPARγ axis.
  19. A metabolite sensor subunit of the Atg1/ULK complex regulates selective autophagy.
  20. The brain area that lights up in prickly people.
  21. Molecular basis of SAP05-mediated ubiquitin-independent proteasomal degradation of transcription factors.
  22. The GATOR2 complex maintains lysosomal-autophagic function by inhibiting the protein degradation of MiT/TFEs.
  23. Remodelling of mitochondrial function by import of specific lipids at multiple membrane-contact sites.
  24. Orientation-invariant autoencoders learn robust representations for shape profiling of cells and organelles.
  25. Resolvin T4 enhances macrophage cholesterol efflux to reduce vascular disease.
  26. Improving polygenic risk prediction in admixed populations by explicitly modeling ancestral-differential effects via GAUDI.
  27. Two-edge-resolved three-dimensional non-line-of-sight imaging with an ordinary camera.
  28. Tigerfish designs oligonucleotide-based in situ hybridization probes targeting intervals of highly repetitive DNA at the scale of genomes.
  29. BCL6 is required for the thymic development of TCRαβ+CD8αα+ intraepithelial lymphocyte lineage.
  30. AMPK phosphorylation of FNIP1 (S220) controls mitochondrial function and muscle fuel utilization during exercise.
  31. Why a cheap, effective treatment for diarrhoea is underused.
  32. Amphiregulin from regulatory T cells promotes liver fibrosis and insulin resistance in non-alcoholic steatohepatitis.
  33. 'It reflects the society we live in where a young person does not feel life is worth living'.
  34. Interorgan rhythmicity as a feature of healthful metabolism.
  35. Isolation and characterization of a pangolin-borne HKU4-related coronavirus that potentially infects human-DPP4-transgenic mice.
  36. Allosteric modulation and G-protein selectivity of the Ca2+-sensing receptor.
  37. Therapeutic mitigation of measles-like immune amnesia and exacerbated disease after prior respiratory virus infections in ferrets.
  38. Connecting clinical and genetic heterogeneity in ADHD.
  39. Local structural preferences in shaping tau amyloid polymorphism.
  40. N2FXm, a method for joint nuclear and cytoplasmic volume measurements, unravels the osmo-mechanical regulation of nuclear volume in mammalian cells.
  41. Aging clock based on nucleosome reorganisation derived from cell-free DNA.
  1. Science. 2024 Feb 09. 383(6683): 674
    The gift of feedback.
    Yaowu Zhang.
      
    DOI:  https://doi.org/10.1126/science.ado4346
  2. Nat Commun. 2024 Feb 08. 15(1): 1204
    The genetic basis of autoimmunity seen through the lens of T cell functional traits.
    Kaitlyn A Lagattuta, Hannah L Park, Laurie Rumker, Kazuyoshi Ishigaki, Aparna Nathan, Soumya Raychaudhuri.
      Autoimmune disease heritability is enriched in T cell-specific regulatory regions of the genome. Modern-day T cell datasets now enable association studies between single nucleotide polymorphisms (SNPs) and a myriad of molecular phenotypes, including chromatin accessibility, gene expression, transcriptional programs, T cell antigen receptor (TCR) amino acid usage, and cell state abundances. Such studies have identified hundreds of quantitative trait loci (QTLs) in T cells that colocalize with genetic risk for autoimmune disease. The key challenge facing immunologists today lies in synthesizing these results toward a unified understanding of the autoimmune T cell: which genes, cell states, and antigens drive tissue destruction?
    DOI:  https://doi.org/10.1038/s41467-024-45170-w
  3. Nat Commun. 2024 Feb 03. 15(1): 1034
    Artesunate treats obesity in male mice and non-human primates through GDF15/GFRAL signalling axis.
    Xuanming Guo, Pallavi Asthana, Lixiang Zhai, Ka Wing Cheng, Susma Gurung, Jiangang Huang, Jiayan Wu, Yijing Zhang, Arun Kumar Mahato, Mart Saarma, Mart Ustav, Hiu Yee Kwan, Aiping Lyu, Kui Ming Chan, Pingyi Xu, Zhao-Xiang Bian, Hoi Leong Xavier Wong.
      Obesity, a global health challenge, is a major risk factor for multiple life-threatening diseases, including diabetes, fatty liver, and cancer. There is an ongoing need to identify safe and tolerable therapeutics for obesity management. Herein, we show that treatment with artesunate, an artemisinin derivative approved by the FDA for the treatment of severe malaria, effectively reduces body weight and improves metabolic profiles in preclinical models of obesity, including male mice with overnutrition-induced obesity and male cynomolgus macaques with spontaneous obesity, without inducing nausea and malaise. Artesunate promotes weight loss and reduces food intake in obese mice and cynomolgus macaques by increasing circulating levels of Growth Differentiation Factor 15 (GDF15), an appetite-regulating hormone with a brainstem-restricted receptor, the GDNF family receptor α-like (GFRAL). Mechanistically, artesunate induces the expression of GDF15 in multiple organs, especially the liver, in mice through a C/EBP homologous protein (CHOP)-directed integrated stress response. Inhibition of GDF15/GFRAL signalling by genetic ablation of GFRAL or tissue-specific knockdown of GDF15 abrogates the anti-obesity effect of artesunate in mice with diet-induced obesity, suggesting that artesunate controls bodyweight and appetite in a GDF15/GFRAL signalling-dependent manner. These data highlight the therapeutic benefits of artesunate in the treatment of obesity and related comorbidities.
    DOI:  https://doi.org/10.1038/s41467-024-45452-3
  4. Nat Commun. 2024 Feb 08. 15(1): 1192
    Protection against overfeeding-induced weight gain is preserved in obesity but does not require FGF21 or MC4R.
    Camilla Lund, Pablo Ranea-Robles, Sarah Falk, Dylan M Rausch, Grethe Skovbjerg, Victoria Kamma Vibe-Petersen, Nathalie Krauth, Jacob Lercke Skytte, Vasiliki Vana, Urmas Roostalu, Tune H Pers, Jens Lund, Christoffer Clemmensen.
      Overfeeding triggers homeostatic compensatory mechanisms that counteract weight gain. Here, we show that both lean and diet-induced obese (DIO) male mice exhibit a potent and prolonged inhibition of voluntary food intake following overfeeding-induced weight gain. We reveal that FGF21 is dispensable for this defense against weight gain. Targeted proteomics unveiled novel circulating factors linked to overfeeding, including the protease  legumain (LGMN). Administration of recombinant LGMN lowers body weight and food intake in DIO mice. The protection against weight gain is also associated with reduced vascularization in the hypothalamus and sustained reductions in the expression of the orexigenic neuropeptide genes, Npy and Agrp, suggesting a role for hypothalamic signaling in this homeostatic recovery from overfeeding. Overfeeding of melanocortin 4 receptor (MC4R) KO mice shows that these mice can suppress voluntary food intake and counteract the enforced weight gain, although their rate of weight recovery is impaired. Collectively, these findings demonstrate that the defense against overfeeding-induced weight gain remains intact in obesity and involves mechanisms independent of both FGF21 and MC4R.
    DOI:  https://doi.org/10.1038/s41467-024-45223-0
  5. Nat Cell Biol. 2024 Feb 06.
    Epithelial zonation along the mouse and human small intestine defines five discrete metabolic domains.
    Rachel K Zwick, Petr Kasparek, Brisa Palikuqi, Sara Viragova, Laura Weichselbaum, Christopher S McGinnis, Kara L McKinley, Asoka Rathnayake, Dedeepya Vaka, Vinh Nguyen, Coralie Trentesaux, Efren Reyes, Alexander R Gupta, Zev J Gartner, Richard M Locksley, James M Gardner, Shalev Itzkovitz, Dario Boffelli, Ophir D Klein.
      A key aspect of nutrient absorption is the exquisite division of labour across the length of the small intestine, with individual nutrients taken up at different proximal:distal positions. For millennia, the small intestine was thought to comprise three segments with indefinite borders: the duodenum, jejunum and ileum. By examining the fine-scale longitudinal transcriptional patterns that span the mouse and human small intestine, we instead identified five domains of nutrient absorption that mount distinct responses to dietary changes, and three regional stem cell populations. Molecular domain identity can be detected with machine learning, which provides a systematic method to computationally identify intestinal domains in mice. We generated a predictive model of transcriptional control of domain identity and validated the roles of Ppar-δ and Cdx1 in patterning lipid metabolism-associated genes. These findings represent a foundational framework for the zonation of absorption across the mammalian small intestine.
    DOI:  https://doi.org/10.1038/s41556-023-01337-z
  6. Nat Commun. 2024 Feb 05. 15(1): 1076
    Identification of myeloid-derived growth factor as a mechanically-induced, growth-promoting angiocrine signal for human hepatocytes.
    Linda Große-Segerath, Paula Follert, Kristina Behnke, Julia Ettich, Tobias Buschmann, Philip Kirschner, Sonja Hartwig, Stefan Lehr, Mortimer Korf-Klingebiel, Daniel Eberhard, Nadja Lehwald-Tywuschik, Hadi Al-Hasani, Wolfram Trudo Knoefel, Stefan Heinrich, Bodo Levkau, Kai C Wollert, Jürgen Scheller, Eckhard Lammert.
      Recently, we have shown that after partial hepatectomy (PHx), an increased hepatic blood flow initiates liver growth in mice by vasodilation and mechanically-triggered release of angiocrine signals. Here, we use mass spectrometry to identify a mechanically-induced angiocrine signal in human hepatic endothelial cells, that is, myeloid-derived growth factor (MYDGF). We show that it induces proliferation and promotes survival of primary human hepatocytes derived from different donors in two-dimensional cell culture, via activation of mitogen-activated protein kinase (MAPK) and signal transducer and activator of transcription 3 (STAT3). MYDGF also enhances proliferation of human hepatocytes in three-dimensional organoids. In vivo, genetic deletion of MYDGF decreases hepatocyte proliferation in the regenerating mouse liver after PHx; conversely, adeno-associated viral delivery of MYDGF increases hepatocyte proliferation and MAPK signaling after PHx. We conclude that MYDGF represents a mechanically-induced angiocrine signal and that it triggers growth of, and provides protection to, primary mouse and human hepatocytes.
    DOI:  https://doi.org/10.1038/s41467-024-44760-y
  7. Nat Cell Biol. 2024 Feb 08.
    mtDNA caught in the act again.
    Kate McArthur, Benjamin T Kile.
      
    DOI:  https://doi.org/10.1038/s41556-024-01345-7
  8. Nat Commun. 2024 Feb 08. 15(1): 1190
    Glucocorticoids increase adiposity by stimulating Krüppel-like factor 9 expression in macrophages.
    Yinliang Zhang, Chunyuan Du, Wei Wang, Wei Qiao, Yuhui Li, Yujie Zhang, Sufang Sheng, Xuenan Zhou, Lei Zhang, Heng Fan, Ying Yu, Yong Chen, Yunfei Liao, Shihong Chen, Yongsheng Chang.
      The mechanisms underlying glucocorticoid (GC)-induced obesity are poorly understood. Macrophages are the primary targets by which GCs exert pharmacological effects and perform critical functions in adipose tissue homeostasis. Here, we show that macrophages are essential for GC-induced obesity. Dexamethasone (Dex) strongly induced Krüppel-like factor 9 (Klf9) expression in macrophages. Similar to Dex, lentivirus-mediated Klf9 overexpression inhibits M1 and M2a markers expression, causing macrophage deactivation. Furthermore, the myeloid-specific Klf9 transgene promotes obesity. Conversely, myeloid-specific Klf9-knockout (mKlf9KO) mice are lean. Moreover, myeloid Klf9 knockout largely blocks obesity induced by chronic GC treatment. Mechanistically, GC-inducible KLF9 recruits the SIN3A/HDAC complex to the promoter regions of Il6, Ptgs2, Il10, Arg1, and Chil3 to inhibit their expression, subsequently reducing thermogenesis and increasing lipid accumulation by inhibiting STAT3 signaling in adipocytes. Thus, KLF9 in macrophages integrates the beneficial anti-inflammatory and adverse metabolic effects of GCs and represents a potential target for therapeutic interventions.
    DOI:  https://doi.org/10.1038/s41467-024-45477-8
  9. Nat Commun. 2024 Feb 06. 15(1): 1096
    Pathogenic NLRP3 mutants form constitutively active inflammasomes resulting in immune-metabolic limitation of IL-1β production.
    Cristina Molina-López, Laura Hurtado-Navarro, Carlos J García, Diego Angosto-Bazarra, Fernando Vallejo, Ana Tapia-Abellán, Joana R Marques-Soares, Carmen Vargas, Segundo Bujan-Rivas, Francisco A Tomás-Barberán, Juan I Arostegui, Pablo Pelegrin.
      Cryopyrin-associated periodic syndrome (CAPS) is an autoinflammatory condition resulting from monoallelic NLRP3 variants that facilitate IL-1β production. Although these are gain-of-function variants characterized by hypersensitivity to cell priming, patients with CAPS and animal models of the disease may present inflammatory flares without identifiable external triggers. Here we find that CAPS-associated NLRP3 variants are forming constitutively active inflammasome, which induce increased basal cleavage of gasdermin D, IL-18 release and pyroptosis, with a concurrent basal pro-inflammatory gene expression signature, including the induction of nuclear receptors 4 A. The constitutively active NLRP3-inflammasome of CAPS is responsive to the selective NLRP3 inhibitor MCC950 and its activation is regulated by deubiquitination. Despite their preactivated state, the CAPS inflammasomes are responsive to activation of the NF-κB pathway. NLRP3-inflammasomes with CAPS-associated variants affect the immunometabolism of the myeloid compartment, leading to disruptions in lipids and amino acid pathways and impaired glycolysis, limiting IL-1β production. In summary, NLRP3 variants causing CAPS form a constitutively active inflammasome inducing pyroptosis and IL-18 release without cell priming, which enables the host's innate defence against pathogens while also limiting IL-1β-dependent inflammatory episodes through immunometabolism modulation.
    DOI:  https://doi.org/10.1038/s41467-024-44990-0
  10. Nature. 2024 Feb 07.
    Convergence of coronary artery disease genes onto endothelial cell programs.
    Gavin R Schnitzler, Helen Kang, Shi Fang, Ramcharan S Angom, Vivian S Lee-Kim, X Rosa Ma, Ronghao Zhou, Tony Zeng, Katherine Guo, Martin S Taylor, Shamsudheen K Vellarikkal, Aurelie E Barry, Oscar Sias-Garcia, Alex Bloemendal, Glen Munson, Philine Guckelberger, Tung H Nguyen, Drew T Bergman, Stephen Hinshaw, Nathan Cheng, Brian Cleary, Krishna Aragam, Eric S Lander, Hilary K Finucane, Debabrata Mukhopadhyay, Rajat M Gupta, Jesse M Engreitz.
      Linking variants from genome-wide association studies (GWAS) to underlying mechanisms of disease remains a challenge1-3. For some diseases, a successful strategy has been to look for cases in which multiple GWAS loci contain genes that act in the same biological pathway1-6. However, our knowledge of which genes act in which pathways is incomplete, particularly for cell-type-specific pathways or understudied genes. Here we introduce a method to connect GWAS variants to functions. This method links variants to genes using epigenomics data, links genes to pathways de novo using Perturb-seq and integrates these data to identify convergence of GWAS loci onto pathways. We apply this approach to study the role of endothelial cells in genetic risk for coronary artery disease (CAD), and discover 43 CAD GWAS signals that converge on the cerebral cavernous malformation (CCM) signalling pathway. Two regulators of this pathway, CCM2 and TLNRD1, are each linked to a CAD risk variant, regulate other CAD risk genes and affect atheroprotective processes in endothelial cells. These results suggest a model whereby CAD risk is driven in part by the convergence of causal genes onto a particular transcriptional pathway in endothelial cells. They highlight shared genes between common and rare vascular diseases (CAD and CCM), and identify TLNRD1 as a new, previously uncharacterized member of the CCM signalling pathway. This approach will be widely useful for linking variants to functions for other common polygenic diseases.
    DOI:  https://doi.org/10.1038/s41586-024-07022-x
  11. Nat Commun. 2024 Feb 05. 15(1): 896
    Bystander activated CD8+ T cells mediate neuropathology during viral infection via antigen-independent cytotoxicity.
    Elizabeth Balint, Emily Feng, Elizabeth C Giles, Tyrah M Ritchie, Alexander S Qian, Fatemeh Vahedi, Amelia Montemarano, Ana L Portillo, Jonathan K Monteiro, Bernardo L Trigatti, Ali A Ashkar.
      Although many viral infections are linked to the development of neurological disorders, the mechanism governing virus-induced neuropathology remains poorly understood, particularly when the virus is not directly neuropathic. Using a mouse model of Zika virus (ZIKV) infection, we found that the severity of neurological disease did not correlate with brain ZIKV titers, but rather with infiltration of bystander activated NKG2D+CD8+ T cells. Antibody depletion of CD8 or blockade of NKG2D prevented ZIKV-associated paralysis, suggesting that CD8+ T cells induce neurological disease independent of TCR signaling. Furthermore, spleen and brain CD8+ T cells exhibited antigen-independent cytotoxicity that correlated with NKG2D expression. Finally, viral infection and inflammation in the brain was necessary but not sufficient to induce neurological damage. We demonstrate that CD8+ T cells mediate virus-induced neuropathology via antigen-independent, NKG2D-mediated cytotoxicity, which may serve as a therapeutic target for treatment of virus-induced neurological disease.
    DOI:  https://doi.org/10.1038/s41467-023-44667-0
  12. Nat Commun. 2024 Feb 09. 15(1): 1229
    T-bet+ B cells are activated by and control endogenous retroviruses through TLR-dependent mechanisms.
    Eileen Rauch, Timm Amendt, Aleksandra Lopez Krol, Fabian B Lang, Vincent Linse, Michelle Hohmann, Ann-Christin Keim, Susanne Kreutzer, Kevin Kawengian, Malte Buchholz, Philipp Duschner, Saskia Grauer, Barbara Schnierle, Andreas Ruhl, Ingo Burtscher, Sonja Dehnert, Chege Kuria, Alexandra Kupke, Stephanie Paul, Thomas Liehr, Marcus Lechner, Markus Schnare, Andreas Kaufmann, Magdalena Huber, Thomas H Winkler, Stefan Bauer, Philipp Yu.
      Endogenous retroviruses (ERVs) are an integral part of the mammalian genome. The role of immune control of ERVs in general is poorly defined as is their function as anti-cancer immune targets or drivers of autoimmune disease. Here, we generate mouse-strains where Moloney-Murine Leukemia Virus tagged with GFP (ERV-GFP) infected the mouse germline. This enables us to analyze the role of genetic, epigenetic and cell intrinsic restriction factors in ERV activation and control. We identify an autoreactive B cell response against the neo-self/ERV antigen GFP as a key mechanism of ERV control. Hallmarks of this response are spontaneous ERV-GFP+ germinal center formation, elevated serum IFN-γ levels and a dependency on Age-associated B cells (ABCs) a subclass of T-bet+ memory B cells. Impairment of IgM B cell receptor-signal in nucleic-acid sensing TLR-deficient mice contributes to defective ERV control. Although ERVs are a part of the genome they break immune tolerance, induce immune surveillance against ERV-derived self-antigens and shape the host immune response.
    DOI:  https://doi.org/10.1038/s41467-024-45201-6
  13. Nat Commun. 2024 Feb 03. 15(1): 1037
    The liver and muscle secreted HFE2-protein maintains central nervous system blood vessel integrity.
    Xue Fan Wang, Robin Vigouroux, Michal Syonov, Yuriy Baglaenko, Angeliki M Nikolakopoulou, Dene Ringuette, Horea Rus, Peter V DiStefano, Suzie Dufour, Alireza P Shabanzadeh, Seunggi Lee, Bernhard K Mueller, Jason Charish, Hidekiyo Harada, Jason E Fish, Joan Wither, Thomas Wälchli, Jean-François Cloutier, Berislav V Zlokovic, Peter L Carlen, Philippe P Monnier.
      Liver failure causes breakdown of the Blood CNS Barrier (BCB) leading to damages of the Central-Nervous-System (CNS), however the mechanisms whereby the liver influences BCB-integrity remain elusive. One possibility is that the liver secretes an as-yet to be identified molecule(s) that circulate in the serum to directly promote BCB-integrity. To study BCB-integrity, we developed light-sheet imaging for three-dimensional analysis. We show that liver- or muscle-specific knockout of Hfe2/Rgmc induces BCB-breakdown, leading to accumulation of toxic-blood-derived fibrinogen in the brain, lower cortical neuron numbers, and behavioral deficits in mice. Soluble HFE2 competes with its homologue RGMa for binding to Neogenin, thereby blocking RGMa-induced downregulation of PDGF-B and Claudin-5 in endothelial cells, triggering BCB-disruption. HFE2 administration in female mice with experimental autoimmune encephalomyelitis, a model for multiple sclerosis, prevented paralysis and immune cell infiltration by inhibiting RGMa-mediated BCB alteration. This study has implications for the pathogenesis and potential treatment of diseases associated with BCB-dysfunction.
    DOI:  https://doi.org/10.1038/s41467-024-45303-1
  14. Cell Res. 2024 Feb 07.
    B cell-reactive triad of B cells, follicular helper and regulatory T cells at homeostasis.
    Yihan Lin, Zurong Wan, Bo Liu, Jiacheng Yao, Tianqi Li, Fang Yang, Jianhua Sui, Yongshan Zhao, Wanli Liu, Xuyu Zhou, Jianbin Wang, Hai Qi.
      Autoreactive B cells are silenced through receptor editing, clonal deletion and anergy induction. Additional autoreactive B cells are ignorant because of physical segregation from their cognate autoantigen. Unexpectedly, we find that follicular B cell-derived autoantigen, including cell surface molecules such as FcγRIIB, is a class of homeostatic autoantigen that can induce spontaneous germinal centers (GCs) and B cell-reactive autoantibodies in non-autoimmune animals with intact T and B cell repertoires. These B cell-reactive B cells form GCs in a manner dependent on spontaneous follicular helper T (TFH) cells, which preferentially recognize B cell-derived autoantigen, and in a manner constrained by spontaneous follicular regulatory T (TFR) cells, which also carry specificities for B cell-derived autoantigen. B cell-reactive GC cells are continuously generated and, following immunization or infection, become intermixed with foreign antigen-induced GCs. Production of plasma cells and antibodies derived from B cell-reactive GC cells are markedly enhanced by viral infection, potentially increasing the chance for autoimmunity. Consequently, immune homeostasis in healthy animals not only involves classical tolerance of silencing and ignoring autoreactive B cells but also entails a reactive equilibrium attained by a spontaneous B cell-reactive triad of B cells, TFH cells and TFR cells.
    DOI:  https://doi.org/10.1038/s41422-024-00929-0
  15. Nat Commun. 2024 Feb 06. 15(1): 1124
    Relaxation of mitochondrial hyperfusion in the diabetic retina via N6-furfuryladenosine confers neuroprotection regardless of glycaemic status.
    Aidan Anderson, Nada Alfahad, Dulani Wimalachandra, Kaouthar Bouzinab, Paula Rudzinska, Heather Wood, Isabel Fazey, Heping Xu, Timothy J Lyons, Nicholas M Barnes, Parth Narendran, Janet M Lord, Saaeha Rauz, Ian G Ganley, Tim M Curtis, Graham R Wallace, Jose R Hombrebueno.
      The recovery of mitochondrial quality control (MQC) may bring innovative solutions for neuroprotection, while imposing a significant challenge given the need of holistic approaches to restore mitochondrial dynamics (fusion/fission) and turnover (mitophagy and biogenesis). In diabetic retinopathy, this is compounded by our lack of understanding of human retinal neurodegeneration, but also how MQC processes interact during disease progression. Here, we show that mitochondria hyperfusion is characteristic of retinal neurodegeneration in human and murine diabetes, blunting the homeostatic turnover of mitochondria and causing metabolic and neuro-inflammatory stress. By mimicking this mitochondrial remodelling in vitro, we ascertain that N6-furfuryladenosine enhances mitochondrial turnover and bioenergetics by relaxing hyperfusion in a controlled fashion. Oral administration of N6-furfuryladenosine enhances mitochondrial turnover in the diabetic mouse retina (Ins2Akita males), improving clinical correlates and conferring neuroprotection regardless of glycaemic status. Our findings provide translational insights for neuroprotection in the diabetic retina through the holistic recovery of MQC.
    DOI:  https://doi.org/10.1038/s41467-024-45387-9
  16. Proc Natl Acad Sci U S A. 2024 Feb 13. 121(7): e2310264121
    DNA hypomethylation ameliorates erosive inflammatory arthritis by modulating interferon regulatory factor-8.
    Gaurav Swarnkar, Nicholas P Semenkovich, Manoj Arra, Dorothy K Mims, Syeda Kanwal Naqvi, Timothy Peterson, Gabriel Mbalaviele, Chia-Lung Wu, Yousef Abu-Amer.
      Epigenetic regulation plays a crucial role in the pathogenesis of autoimmune diseases such as inflammatory arthritis. DNA hypomethylating agents, such as decitabine (DAC), have been shown to dampen inflammation and restore immune homeostasis. In the present study, we demonstrate that DAC elicits potent anti-inflammatory effects and attenuates disease symptoms in several animal models of arthritis. Transcriptomic and epigenomic profiling show that DAC-mediated hypomethylation regulates a wide range of cell types in arthritis, altering the differentiation trajectories of anti-inflammatory macrophage populations, regulatory T cells, and tissue-protective synovial fibroblasts (SFs). Mechanistically, DAC-mediated demethylation of intragenic 5'-Cytosine phosphate Guanine-3' (CpG) islands of the transcription factor Irf8 (interferon regulatory factor 8) induced its re-expression and promoted its repressor activity. As a result, DAC restored joint homeostasis by resetting the transcriptomic signature of negative regulators of inflammation in synovial macrophages (MerTK, Trem2, and Cx3cr1), TREGs (Foxp3), and SFs (Pdpn and Fapα). In conclusion, we found that Irf8 is necessary for the inhibitory effect of DAC in murine arthritis and that direct expression of Irf8 is sufficient to significantly mitigate arthritis.
    Keywords:  Irf8; arthritis; decitabine; methylation; osteolysis
    DOI:  https://doi.org/10.1073/pnas.2310264121
  17. Science. 2024 Feb 09. 383(6683): 589-590
    Time for growth.
    Christopher R Buckley, Michael J Haydon.
      Plants measure the duration of metabolic activity to promote rapid growth in long days.
    DOI:  https://doi.org/10.1126/science.adn5189
  18. Nat Commun. 2024 Feb 03. 15(1): 1024
    5-aminosalicylic acid suppresses osteoarthritis through the OSCAR-PPARγ axis.
    Jihee Kim, Gina Ryu, Jeongmin Seo, Miyeon Go, Gyungmin Kim, Sol Yi, Suwon Kim, Hana Lee, June-Yong Lee, Han Sung Kim, Min-Chan Park, Dong Hae Shin, Hyunbo Shim, Wankyu Kim, Soo Young Lee.
      Osteoarthritis (OA) is a progressive and irreversible degenerative joint disease that is characterized by cartilage destruction, osteophyte formation, subchondral bone remodeling, and synovitis. Despite affecting millions of patients, effective and safe disease-modifying osteoarthritis drugs are lacking. Here we reveal an unexpected role for the small molecule 5-aminosalicylic acid (5-ASA), which is used as an anti-inflammatory drug in ulcerative colitis. We show that 5-ASA competes with extracellular-matrix collagen-II to bind to osteoclast-associated receptor (OSCAR) on chondrocytes. Intra-articular 5-ASA injections ameliorate OA generated by surgery-induced medial-meniscus destabilization in male mice. Significantly, this effect is also observed when 5-ASA was administered well after OA onset. Moreover, mice with DMM-induced OA that are treated with 5-ASA at weeks 8-11 and sacrificed at week 12 have thicker cartilage than untreated mice that were sacrificed at week 8. Mechanistically, 5-ASA reverses OSCAR-mediated transcriptional repression of PPARγ in articular chondrocytes, thereby suppressing COX-2-related inflammation. It also improves chondrogenesis, strongly downregulates ECM catabolism, and promotes ECM anabolism. Our results suggest that 5-ASA could serve as a DMOAD.
    DOI:  https://doi.org/10.1038/s41467-024-45174-6
  19. Nat Cell Biol. 2024 Feb 05.
    A metabolite sensor subunit of the Atg1/ULK complex regulates selective autophagy.
    A S Gross, R Ghillebert, M Schuetter, E Reinartz, A Rowland, B C Bishop, M Stumpe, J Dengjel, M Graef.
      Cells convert complex metabolic information into stress-adapted autophagy responses. Canonically, multilayered protein kinase networks converge on the conserved Atg1/ULK kinase complex (AKC) to induce non-selective and selective forms of autophagy in response to metabolic changes. Here we show that, upon phosphate starvation, the metabolite sensor Pho81 interacts with the adaptor subunit Atg11 at the AKC via an Atg11/FIP200 interaction motif to modulate pexophagy by virtue of its conserved phospho-metabolite sensing SPX domain. Notably, core AKC components Atg13 and Atg17 are dispensable for phosphate starvation-induced autophagy revealing significant compositional and functional plasticity of the AKC. Our data indicate that, instead of functioning as a selective autophagy receptor, Pho81 compensates for partially inactive Atg13 by promoting Atg11 phosphorylation by Atg1 critical for pexophagy during phosphate starvation. Our work shows Atg11/FIP200 adaptor subunits bind not only selective autophagy receptors but also modulator subunits that convey metabolic information directly to the AKC for autophagy regulation.
    DOI:  https://doi.org/10.1038/s41556-024-01348-4
  20. Nature. 2024 Feb 05.
    The brain area that lights up in prickly people.
      
    Keywords:  Neuroscience
    DOI:  https://doi.org/10.1038/d41586-024-00318-y
  21. Nat Commun. 2024 Feb 08. 15(1): 1170
    Molecular basis of SAP05-mediated ubiquitin-independent proteasomal degradation of transcription factors.
    Xiaojie Yan, Xinxin Yuan, Jianke Lv, Bing Zhang, Yongle Huang, Qianqian Li, Jinfeng Ma, Yanran Li, Xiaolu Wang, Yao Li, Ying Yu, Quanyan Liu, Tong Liu, Wenyi Mi, Cheng Dong.
      SAP05, a secreted effector by the obligate parasitic bacteria phytoplasma, bridges host SPL and GATA transcription factors (TFs) to the 26 S proteasome subunit RPN10 for ubiquitination-independent degradation. Here, we report the crystal structures of SAP05 in complex with SPL5, GATA18 and RPN10, which provide detailed insights into the protein-protein interactions involving SAP05. SAP05 employs two opposing lobes with an acidic path and a hydrophobic path to contact TFs and RPN10, respectively. Our crystal structures, in conjunction with mutagenesis and degradation assays, reveal that SAP05 targets plant GATAs but not animal GATAs dependent on their direct salt-bridged electrostatic interactions. Additionally, SAP05 hijacks plant RPN10 but not animal RPN10 due to structural steric hindrance and the key hydrophobic interactions. This study provides valuable molecular-level information into the modulation of host proteins to prevent insect-borne diseases.
    DOI:  https://doi.org/10.1038/s41467-024-45521-7
  22. Mol Cell. 2024 Jan 31. pii: S1097-2765(24)00048-0. [Epub ahead of print]
    The GATOR2 complex maintains lysosomal-autophagic function by inhibiting the protein degradation of MiT/TFEs.
    Shu Yang, Chun-Yuan Ting, Mary A Lilly.
      Lysosomes are central to metabolic homeostasis. The microphthalmia bHLH-LZ transcription factors (MiT/TFEs) family members MITF, TFEB, and TFE3 promote the transcription of lysosomal and autophagic genes and are often deregulated in cancer. Here, we show that the GATOR2 complex, an activator of the metabolic regulator TORC1, maintains lysosomal function by protecting MiT/TFEs from proteasomal degradation independent of TORC1, GATOR1, and the RAG GTPase. We determine that in GATOR2 knockout HeLa cells, members of the MiT/TFEs family are ubiquitylated by a trio of E3 ligases and are degraded, resulting in lysosome dysfunction. Additionally, we demonstrate that GATOR2 protects MiT/TFE proteins in pancreatic ductal adenocarcinoma and Xp11 translocation renal cell carcinoma, two cancers that are driven by MiT/TFE hyperactivation. In summary, we find that the GATOR2 complex has independent roles in TORC1 regulation and MiT/TFE protein protection and thus is central to coordinating cellular metabolism with control of the lysosomal-autophagic system.
    Keywords:  E3 ligases; GATOR2; MiT/TFEs; TORC1; autophagy; lysosome; pancreatic ductal adenocarcinoma; renal cell carcinoma; ubiquitination
    DOI:  https://doi.org/10.1016/j.molcel.2024.01.012
  23. FEBS Lett. 2024 Feb 04.
    Remodelling of mitochondrial function by import of specific lipids at multiple membrane-contact sites.
    Aksel J Saukko-Paavola, Robin W Klemm.
      Organelles form physical and functional contact between each other to exchange information, metabolic intermediates, and signaling molecules. Tethering factors and contact site complexes bring partnering organelles into close spatial proximity to establish membrane contact sites (MCSs), which specialize in unique functions like lipid transport or Ca2+ signaling. Here, we discuss how MCSs form dynamic platforms that are important for lipid metabolism. We provide a perspective on how import of specific lipids from the ER and other organelles may contribute to remodeling of mitochondria during nutrient starvation. We speculate that mitochondrial adaptation is achieved by connecting several compartments into a highly dynamic organelle network. The lipid droplet appears to be a central hub in coordinating the function of these organelle neighborhoods.
    Keywords:  autophagy; endoplasmic reticulum (ER); lipid droplets (LDs); membrane contact sites; metabolic adaptation; mitochondria; mitochondrial shape; organelle-network; starvation
    DOI:  https://doi.org/10.1002/1873-3468.14813
  24. Nat Commun. 2024 Feb 03. 15(1): 1022
    Orientation-invariant autoencoders learn robust representations for shape profiling of cells and organelles.
    James Burgess, Jeffrey J Nirschl, Maria-Clara Zanellati, Alejandro Lozano, Sarah Cohen, Serena Yeung-Levy.
      Cell and organelle shape are driven by diverse genetic and environmental factors and thus accurate quantification of cellular morphology is essential to experimental cell biology. Autoencoders are a popular tool for unsupervised biological image analysis because they learn a low-dimensional representation that maps images to feature vectors to generate a semantically meaningful embedding space of morphological variation. The learned feature vectors can also be used for clustering, dimensionality reduction, outlier detection, and supervised learning problems. Shape properties do not change with orientation, and thus we argue that representation learning methods should encode this orientation invariance. We show that conventional autoencoders are sensitive to orientation, which can lead to suboptimal performance on downstream tasks. To address this, we develop O2-variational autoencoder (O2-VAE), an unsupervised method that learns robust, orientation-invariant representations. We use O2-VAE to discover morphology subgroups in segmented cells and mitochondria, detect outlier cells, and rapidly characterise cellular shape and texture in large datasets, including in a newly generated synthetic benchmark.
    DOI:  https://doi.org/10.1038/s41467-024-45362-4
  25. Nat Commun. 2024 Feb 05. 15(1): 975
    Resolvin T4 enhances macrophage cholesterol efflux to reduce vascular disease.
    Mary E Walker, Roberta De Matteis, Mauro Perretti, Jesmond Dalli.
      While cardiovascular disease (CVD) is one of the major co-morbidities in patients with rheumatoid arthritis (RA), the mechanism(s) that contribute to CVD in patients with RA remain to be fully elucidated. Herein, we observe that plasma concentrations of 13-series resolvin (RvT)4 negatively correlate with vascular lipid load in mouse inflammatory arthritis. Administration of RvT4 to male arthritic mice fed an atherogenic diet significantly reduces atherosclerosis. Assessment of the mechanisms elicited by this mediator demonstrates that RvT4 activates cholesterol efflux in lipid laden macrophages via a Scavenger Receptor class B type 1 (SR-BI)-Neutral Cholesterol Ester Hydrolase-dependent pathway. This leads to the reprogramming of lipid laden macrophages yielding tissue protection. Pharmacological inhibition or knockdown of macrophage SR-BI reverses the vasculo-protective activities of RvT4 in vitro and in male mice in vivo. Together these findings elucidate a RvT4-SR-BI centered mechanism that orchestrates macrophage responses to limit atherosclerosis during inflammatory arthritis.
    DOI:  https://doi.org/10.1038/s41467-024-44868-1
  26. Nat Commun. 2024 Feb 03. 15(1): 1016
    Improving polygenic risk prediction in admixed populations by explicitly modeling ancestral-differential effects via GAUDI.
    Quan Sun, Bryce T Rowland, Jiawen Chen, Anna V Mikhaylova, Christy Avery, Ulrike Peters, Jessica Lundin, Tara Matise, Steve Buyske, Ran Tao, Rasika A Mathias, Alexander P Reiner, Paul L Auer, Nancy J Cox, Charles Kooperberg, Timothy A Thornton, Laura M Raffield, Yun Li.
      Polygenic risk scores (PRS) have shown successes in clinics, but most PRS methods focus only on participants with distinct primary continental ancestry without accommodating recently-admixed individuals with mosaic continental ancestry backgrounds for different segments of their genomes. Here, we develop GAUDI, a novel penalized-regression-based method specifically designed for admixed individuals. GAUDI explicitly models ancestry-differential effects while borrowing information across segments with shared ancestry in admixed genomes. We demonstrate marked advantages of GAUDI over other methods through comprehensive simulation and real data analyses for traits with associated variants exhibiting ancestral-differential effects. Leveraging data from the Women's Health Initiative study, we show that GAUDI improves PRS prediction of white blood cell count and C-reactive protein in African Americans by > 64% compared to alternative methods, and even outperforms PRS-CSx with large European GWAS for some scenarios. We believe GAUDI will be a valuable tool to mitigate disparities in PRS performance in admixed individuals.
    DOI:  https://doi.org/10.1038/s41467-024-45135-z
  27. Nat Commun. 2024 Feb 07. 15(1): 1162
    Two-edge-resolved three-dimensional non-line-of-sight imaging with an ordinary camera.
    Robinson Czajkowski, John Murray-Bruce.
      We introduce an approach for three-dimensional full-colour non-line-of-sight imaging with an ordinary camera that relies on a complementary combination of a new measurement acquisition strategy, scene representation model, and tailored reconstruction method. From an ordinary photograph of a matte line-of-sight surface illuminated by the hidden scene, our approach reconstructs a three-dimensional image of the scene hidden behind an occluding structure by exploiting two orthogonal edges of the structure for transverse resolution along azimuth and elevation angles and an information orthogonal scene representation for accurate range resolution. Prior demonstrations beyond two-dimensional reconstructions used expensive, specialized optical systems to gather information about the hidden scene. Here, we achieve accurate three-dimensional imaging using inexpensive, and ubiquitous hardware, without requiring a calibration image. Thus, our system may find use in indoor situations like reconnaissance and search-and-rescue.
    DOI:  https://doi.org/10.1038/s41467-024-45397-7
  28. Nat Commun. 2024 Feb 03. 15(1): 1027
    Tigerfish designs oligonucleotide-based in situ hybridization probes targeting intervals of highly repetitive DNA at the scale of genomes.
    Robin Aguilar, Conor K Camplisson, Qiaoyi Lin, Karen H Miga, William S Noble, Brian J Beliveau.
      Fluorescent in situ hybridization (FISH) is a powerful method for the targeted visualization of nucleic acids in their native contexts. Recent technological advances have leveraged computationally designed oligonucleotide (oligo) probes to interrogate > 100 distinct targets in the same sample, pushing the boundaries of FISH-based assays. However, even in the most highly multiplexed experiments, repetitive DNA regions are typically not included as targets, as the computational design of specific probes against such regions presents significant technical challenges. Consequently, many open questions remain about the organization and function of highly repetitive sequences. Here, we introduce Tigerfish, a software tool for the genome-scale design of oligo probes against repetitive DNA intervals. We showcase Tigerfish by designing a panel of 24 interval-specific repeat probes specific to each of the 24 human chromosomes and imaging this panel on metaphase spreads and in interphase nuclei. Tigerfish extends the powerful toolkit of oligo-based FISH to highly repetitive DNA.
    DOI:  https://doi.org/10.1038/s41467-024-45385-x
  29. Sci Immunol. 2024 Sep 02. 9(92): eadk4348
    BCL6 is required for the thymic development of TCRαβ+CD8αα+ intraepithelial lymphocyte lineage.
    Qi Xing, Dehui Chang, Shiyuan Xie, Xiaohong Zhao, Hao Zhang, Xiaohu Wang, Xue Bai, Chen Dong.
      TCRαβ+CD8αα+ intraepithelial lymphocytes (CD8αα+ αβ IELs) are a specialized subset of T cells in the gut epithelium that develop from thymic agonist selected IEL precursors (IELps). The molecular mechanisms underlying the selection and differentiation of this T cell type in the thymus are largely unknown. Here, we found that Bcl6 deficiency in αβ T cells resulted in the near absence of CD8αα+ αβ IELs. BCL6 was expressed by approximately 50% of CD8αα+ αβ IELs and by the majority of thymic PD1+ IELps after agonist selection. Bcl6 deficiency blocked early IELp generation in the thymus, and its expression in IELps was induced by thymic TCR signaling in an ERK-dependent manner. As a result of Bcl6 deficiency, the precursors of IELps among CD4+CD8+ double-positive thymocytes exhibited increased apoptosis during agonist selection and impaired IELp differentiation and maturation. Together, our results elucidate BCL6 as a crucial transcription factor during the thymic development of CD8αα+ αβ IELs.
    DOI:  https://doi.org/10.1126/sciimmunol.adk4348
  30. Sci Adv. 2024 Feb 09. 10(6): eadj2752
    AMPK phosphorylation of FNIP1 (S220) controls mitochondrial function and muscle fuel utilization during exercise.
    Liwei Xiao, Yujing Yin, Zongchao Sun, Jing Liu, Yuhuan Jia, Likun Yang, Yan Mao, Shujun Peng, Zhifu Xie, Lei Fang, Jingya Li, Xiaoduo Xie, Zhenji Gan.
      Exercise-induced activation of adenosine monophosphate-activated protein kinase (AMPK) and substrate phosphorylation modulate the metabolic capacity of mitochondria in skeletal muscle. However, the key effector(s) of AMPK and the regulatory mechanisms remain unclear. Here, we showed that AMPK phosphorylation of the folliculin interacting protein 1 (FNIP1) serine-220 (S220) controls mitochondrial function and muscle fuel utilization during exercise. Loss of FNIP1 in skeletal muscle resulted in increased mitochondrial content and augmented metabolic capacity, leading to enhanced exercise endurance in mice. Using skeletal muscle-specific nonphosphorylatable FNIP1 (S220A) and phosphomimic (S220D) transgenic mouse models as well as biochemical analysis in primary skeletal muscle cells, we demonstrated that exercise-induced FNIP1 (S220) phosphorylation by AMPK in muscle regulates mitochondrial electron transfer chain complex assembly, fuel utilization, and exercise performance without affecting mechanistic target of rapamycin complex 1-transcription factor EB signaling. Therefore, FNIP1 is a multifunctional AMPK effector for mitochondrial adaptation to exercise, implicating a mechanism for exercise tolerance in health and disease.
    DOI:  https://doi.org/10.1126/sciadv.adj2752
  31. Nature. 2024 Feb 08.
    Why a cheap, effective treatment for diarrhoea is underused.
    Smriti Mallapaty.
      
    Keywords:  Epidemiology; Infection; Public health
    DOI:  https://doi.org/10.1038/d41586-024-00351-x
  32. Immunity. 2024 Jan 29. pii: S1074-7613(24)00034-7. [Epub ahead of print]
    Amphiregulin from regulatory T cells promotes liver fibrosis and insulin resistance in non-alcoholic steatohepatitis.
    Thomas M Savage, Katherine T Fortson, Kenia de Los Santos-Alexis, Angelica Oliveras-Alsina, Mathieu Rouanne, Sarah S Rae, Jennifer R Gamarra, Hani Shayya, Adam Kornberg, Renzo Cavero, Fangda Li, Arnold Han, Rebecca A Haeusler, Julien Adam, Robert F Schwabe, Nicholas Arpaia.
      Production of amphiregulin (Areg) by regulatory T (Treg) cells promotes repair after acute tissue injury. Here, we examined the function of Treg cells in non-alcoholic steatohepatitis (NASH), a setting of chronic liver injury. Areg-producing Treg cells were enriched in the livers of mice and humans with NASH. Deletion of Areg in Treg cells, but not in myeloid cells, reduced NASH-induced liver fibrosis. Chronic liver damage induced transcriptional changes associated with Treg cell activation. Mechanistically, Treg cell-derived Areg activated pro-fibrotic transcriptional programs in hepatic stellate cells via epidermal growth factor receptor (EGFR) signaling. Deletion of Areg in Treg cells protected mice from NASH-dependent glucose intolerance, which also was dependent on EGFR signaling on hepatic stellate cells. Areg from Treg cells promoted hepatocyte gluconeogenesis through hepatocyte detection of hepatic stellate cell-derived interleukin-6. Our findings reveal a maladaptive role for Treg cell-mediated tissue repair functions in chronic liver disease and link liver damage to NASH-dependent glucose intolerance.
    Keywords:  NASH; Tregs; insulin resistance; liver fibrosis; non-alcoholic steatohepatitis; regulatory T cells
    DOI:  https://doi.org/10.1016/j.immuni.2024.01.009
  33. Nature. 2024 Feb 09.
    'It reflects the society we live in where a young person does not feel life is worth living'.
    Dom Byrne.
      
    Keywords:  Careers; Health care; Policy; Public health
    DOI:  https://doi.org/10.1038/d41586-024-00210-9
  34. Cell Metab. 2024 Jan 31. pii: S1550-4131(24)00009-3. [Epub ahead of print]
    Interorgan rhythmicity as a feature of healthful metabolism.
    Joseph Bass.
      The finding that animals with circadian gene mutations exhibit diet-induced obesity and metabolic syndrome with hypoinsulinemia revealed a distinct role for the clock in the brain and peripheral tissues. Obesogenic diets disrupt rhythmic sleep/wake patterns, feeding behavior, and transcriptional networks, showing that metabolic signals reciprocally control the clock. Providing access to high-fat diet only during the sleep phase (light period) in mice accelerates weight gain, whereas isocaloric time-restricted feeding during the active period enhances energy expenditure due to circadian induction of adipose thermogenesis. This perspective focuses on advances and unanswered questions in understanding the interorgan circadian control of healthful metabolism.
    Keywords:  circadian; diabetes; epigenetics; insulin; metabolism; molecular clock; obesity; sleep; thermogenesis; transcription
    DOI:  https://doi.org/10.1016/j.cmet.2024.01.009
  35. Nat Commun. 2024 Feb 05. 15(1): 1048
    Isolation and characterization of a pangolin-borne HKU4-related coronavirus that potentially infects human-DPP4-transgenic mice.
    Luo-Yuan Xia, Zhen-Fei Wang, Xiao-Ming Cui, Yuan-Guo Li, Run-Ze Ye, Dai-Yun Zhu, Fang-Xu Li, Jie Zhang, Wen-Hao Wang, Ming-Zhu Zhang, Wan-Ying Gao, Lian-Feng Li, Teng-Cheng Que, Tie-Cheng Wang, Na Jia, Jia-Fu Jiang, Yu-Wei Gao, Wu-Chun Cao.
      We recently detected a HKU4-related coronavirus in subgenus Merbecovirus (named pangolin-CoV-HKU4-P251T) from a Malayan pangolin1. Here we report isolation and characterization of pangolin-CoV-HKU4-P251T, the genome sequence of which is closest to that of a coronavirus from the greater bamboo bat (Tylonycteris robustula) in Yunnan Province, China, with a 94.3% nucleotide identity. Pangolin-CoV-HKU4-P251T is able to infect human cell lines, and replicates more efficiently in cells that express human-dipeptidyl-peptidase-4 (hDPP4)-expressing and pangolin-DPP4-expressing cells than in bat-DPP4-expressing cells. After intranasal inoculation with pangolin-CoV-HKU4-P251, hDPP4-transgenic female mice are likely infected, showing persistent viral RNA copy numbers in the lungs. Progressive interstitial pneumonia developed in the infected mice, characterized by the accumulation of macrophages, and increase of antiviral cytokines, proinflammatory cytokines, and chemokines in lung tissues. These findings suggest that the pangolin-borne HKU4-related coronavirus has a potential for emerging as a human pathogen by using hDPP4.
    DOI:  https://doi.org/10.1038/s41467-024-45453-2
  36. Nature. 2024 Feb 07.
    Allosteric modulation and G-protein selectivity of the Ca2+-sensing receptor.
    Feng He, Cheng-Guo Wu, Yang Gao, Sabrina N Rahman, Magda Zaoralová, Makaía M Papasergi-Scott, Ting-Jia Gu, Michael J Robertson, Alpay B Seven, Lingjun Li, Jesper M Mathiesen, Georgios Skiniotis.
      The calcium-sensing receptor (CaSR) is a family C G-protein-coupled receptor1 (GPCR) that has a central role in regulating systemic calcium homeostasis2,3. Here we use cryo-electron microscopy and functional assays to investigate the activation of human CaSR embedded in lipid nanodiscs and its coupling to functional Gi versus Gq proteins in the presence and absence of the calcimimetic drug cinacalcet. High-resolution structures show that both Gi and Gq drive additional conformational changes in the activated CaSR dimer to stabilize a more extensive asymmetric interface of the seven-transmembrane domain (7TM) that involves key protein-lipid interactions. Selective Gi and Gq coupling by the receptor is achieved through substantial rearrangements of intracellular loop 2 and the C terminus, which contribute differentially towards the binding of the two G-protein subtypes, resulting in distinct CaSR-G-protein interfaces. The structures also reveal that natural polyamines target multiple sites on CaSR to enhance receptor activation by zipping negatively charged regions between two protomers. Furthermore, we find that the amino acid L-tryptophan, a well-known ligand of CaSR extracellular domains, occupies the 7TM bundle of the G-protein-coupled protomer at the same location as cinacalcet and other allosteric modulators. Together, these results provide a framework for G-protein activation and selectivity by CaSR, as well as its allosteric modulation by endogenous and exogenous ligands.
    DOI:  https://doi.org/10.1038/s41586-024-07055-2
  37. Nat Commun. 2024 Feb 08. 15(1): 1189
    Therapeutic mitigation of measles-like immune amnesia and exacerbated disease after prior respiratory virus infections in ferrets.
    Robert M Cox, Josef D Wolf, Nicole A Lieberman, Carolin M Lieber, Hae-Ji Kang, Zachary M Sticher, Jeong-Joong Yoon, Meghan K Andrews, Mugunthan Govindarajan, Rebecca E Krueger, Elizabeth B Sobolik, Michael G Natchus, Andrew T Gewirtz, Rik L deSwart, Alexander A Kolykhalov, Khan Hekmatyar, Kaori Sakamoto, Alexander L Greninger, Richard K Plemper.
      Measles cases have surged pre-COVID-19 and the pandemic has aggravated the problem. Most measles-associated morbidity and mortality arises from destruction of pre-existing immune memory by measles virus (MeV), a paramyxovirus of the morbillivirus genus. Therapeutic measles vaccination lacks efficacy, but little is known about preserving immune memory through antivirals and the effect of respiratory disease history on measles severity. We use a canine distemper virus (CDV)-ferret model as surrogate for measles and employ an orally efficacious paramyxovirus polymerase inhibitor to address these questions. A receptor tropism-intact recombinant CDV with low lethality reveals an 8-day advantage of antiviral treatment versus therapeutic vaccination in maintaining immune memory. Infection of female ferrets with influenza A virus (IAV) A/CA/07/2009 (H1N1) or respiratory syncytial virus (RSV) four weeks pre-CDV causes fatal hemorrhagic pneumonia with lung onslaught by commensal bacteria. RNAseq identifies CDV-induced overexpression of trefoil factor (TFF) peptides in the respiratory tract, which is absent in animals pre-infected with IAV. Severe outcomes of consecutive IAV/CDV infections are mitigated by oral antivirals even when initiated late. These findings validate the morbillivirus immune amnesia hypothesis, define measles treatment paradigms, and identify priming of the TFF axis through prior respiratory infections as risk factor for exacerbated morbillivirus disease.
    DOI:  https://doi.org/10.1038/s41467-024-45418-5
  38. Nat Genet. 2024 Feb 06.
    Connecting clinical and genetic heterogeneity in ADHD.
    Chloe X Yap, Jacob Gratten.
      
    DOI:  https://doi.org/10.1038/s41588-024-01652-7
  39. Nat Commun. 2024 Feb 03. 15(1): 1028
    Local structural preferences in shaping tau amyloid polymorphism.
    Nikolaos Louros, Martin Wilkinson, Grigoria Tsaka, Meine Ramakers, Chiara Morelli, Teresa Garcia, Rodrigo Gallardo, Sam D'Haeyer, Vera Goossens, Dominique Audenaert, Dietmar Rudolf Thal, Ian R Mackenzie, Rosa Rademakers, Neil A Ranson, Sheena E Radford, Frederic Rousseau, Joost Schymkowitz.
      Tauopathies encompass a group of neurodegenerative disorders characterised by diverse tau amyloid fibril structures. The persistence of polymorphism across tauopathies suggests that distinct pathological conditions dictate the adopted polymorph for each disease. However, the extent to which intrinsic structural tendencies of tau amyloid cores contribute to fibril polymorphism remains uncertain. Using a combination of experimental approaches, we here identify a new amyloidogenic motif, PAM4 (Polymorphic Amyloid Motif of Repeat 4), as a significant contributor to tau polymorphism. Calculation of per-residue contributions to the stability of the fibril cores of different pathologic tau structures suggests that PAM4 plays a central role in preserving structural integrity across amyloid polymorphs. Consistent with this, cryo-EM structural analysis of fibrils formed from a synthetic PAM4 peptide shows that the sequence adopts alternative structures that closely correspond to distinct disease-associated tau strains. Furthermore, in-cell experiments revealed that PAM4 deletion hampers the cellular seeding efficiency of tau aggregates extracted from Alzheimer's disease, corticobasal degeneration, and progressive supranuclear palsy patients, underscoring PAM4's pivotal role in these tauopathies. Together, our results highlight the importance of the intrinsic structural propensity of amyloid core segments to determine the structure of tau in cells, and in propagating amyloid structures in disease.
    DOI:  https://doi.org/10.1038/s41467-024-45429-2
  40. Nat Commun. 2024 Feb 07. 15(1): 1070
    N2FXm, a method for joint nuclear and cytoplasmic volume measurements, unravels the osmo-mechanical regulation of nuclear volume in mammalian cells.
    Fabrizio A Pennacchio, Alessandro Poli, Francesca Michela Pramotton, Stefania Lavore, Ilaria Rancati, Mario Cinquanta, Daan Vorselen, Elisabetta Prina, Orso Maria Romano, Aldo Ferrari, Matthieu Piel, Marco Cosentino Lagomarsino, Paolo Maiuri.
      In eukaryotes, cytoplasmic and nuclear volumes are tightly regulated to ensure proper cell homeostasis. However, current methods to measure cytoplasmic and nuclear volumes, including confocal 3D reconstruction, have limitations, such as relying on two-dimensional projections or poor vertical resolution. Here, to overcome these limitations, we describe a method, N2FXm, to jointly measure cytoplasmic and nuclear volumes in single cultured adhering human cells, in real time, and across cell cycles. We find that this method accurately provides joint size over dynamic measurements and at different time resolutions. Moreover, by combining several experimental perturbations and analyzing a mathematical model including osmotic effects and tension, we show that N2FXm can give relevant insights on how mechanical forces exerted by the cytoskeleton on the nuclear envelope can affect the growth of nucleus volume by biasing nuclear import. Our method, by allowing for accurate joint nuclear and cytoplasmic volume dynamic measurements at different time resolutions, highlights the non-constancy of the nucleus/cytoplasm ratio along the cell cycle.
    DOI:  https://doi.org/10.1038/s41467-024-45168-4
  41. Aging Cell. 2024 Feb 09. e14100
    Aging clock based on nucleosome reorganisation derived from cell-free DNA.
    Mariya Shtumpf, Seihee Jeong, Milena Bikova, Hulkar Mamayusupova, Luminita Ruje, Vladimir B Teif.
      Aging induces systematic changes in the distribution of nucleosomes, which affect gene expression programs. Here we reconstructed nucleosome maps based on cell-free DNA (cfDNA) extracted from blood plasma using four cohorts of people of different ages. We show that nucleosomes tend to be separated by larger genomic distances in older people, and age correlates with the nucleosome repeat length (NRL). Furthermore, we developed the first aging clock based on cfDNA nucleosomics. Machine learning based on cfDNA distance distributions allowed predicting person's age with the median absolute error of 3-3.5 years.
    Keywords:  NRL; aging; cell-free DNA; cfDNA; liquid biopsy; nucleosome positioning; nucleosome repeat length; nucleosomics
    DOI:  https://doi.org/10.1111/acel.14100
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