bims-nimamd Biomed News
on Neuroimmunity and neuroinflammation in ageing and metabolic disease
Issue of 2025–01–05
thirty-one papers selected by
Fawaz Alzaïd, Sorbonne Université
  1. Restoring aging-related tissue homeostasis via reactivated innate immunotherapy.
  2. FBP1 controls liver cancer evolution from senescent MASH hepatocytes.
  3. Spatial transcriptomics of healthy and fibrotic human liver at single-cell resolution.
  4. Latent HIV-1 induction.
  5. Innate immune barrier against oncogenic transformation.
  6. Past interactions of T cells with antigens shape CAR T cell responses.
  7. Fast and sensitive multivalent spatial pattern-recognition for circular RNA detection.
  8. AMPK-regulated glycerol excretion maintains metabolic crosstalk between reductive and energetic stress.
  9. DNA end sensing and cleavage by the Shedu anti-phage defense system.
  10. The T cell receptor sequence influences the likelihood of T cell memory formation.
  11. Global organelle profiling reveals subcellular localization and remodeling at proteome scale.
  12. Mammalian SLC39A13 promotes ER/Golgi iron transport and iron homeostasis in multiple compartments.
  13. Paradoxical link between senescent cell state and liver cancer resolved.
  14. Genetic insights into global heterogeneity of type 2 diabetes.
  15. Chk2 sustains PLK1 activity in mitosis to ensure proper chromosome segregation.
  16. Platelet partnerships and lasting memories.
  17. diaTracer enables spectrum-centric analysis of diaPASEF proteomics data.
  18. Monoallelic expression can govern penetrance of inborn errors of immunity.
  19. NET formation-mediated in situ protein delivery to the inflamed central nervous system.
  20. Integrated multi-omics profiling reveals neutrophil extracellular traps potentiate Aortic dissection progression.
  21. The chromatin remodeling factor OsINO80 promotes H3K27me3 and H3K9me2 deposition and maintains TE silencing in rice.
  22. Mms22-Rtt107 axis attenuates the DNA damage checkpoint and the stability of the Rad9 checkpoint mediator.
  23. The Cryo-EM structure of human CD163 bound to haptoglobin-hemoglobin reveals molecular mechanisms of hemoglobin scavenging.
  24. OSP-1 protects neurons from autophagic cell death induced by acute oxidative stress.
  25. Brainstem BDNF neurons are downstream of GFRAL/GLP1R signalling.
  26. A high-protein diet-responsive gut hormone regulates behavioral and metabolic optimization in Drosophila melanogaster.
  27. Alcohol-induced gut microbial reorganization and associated overproduction of phenylacetylglutamine promotes cardiovascular disease.
  28. Anti-CTLA4 treatment reduces lymphedema risk potentially through a systemic expansion of the FOXP3+ Treg population.
  29. G6PC2 controls glucagon secretion by defining the set point for glucose in pancreatic α cells.
  30. Cooperative integration of spatially resolved multi-omics data with COSMOS.
  31. Nuclear speckles regulate functional programs in cancer.
  1. Nat Aging. 2025 Jan 02.
    Restoring aging-related tissue homeostasis via reactivated innate immunotherapy.
      
    DOI:  https://doi.org/10.1038/s43587-024-00782-1
  2. Nature. 2025 Jan 01.
    FBP1 controls liver cancer evolution from senescent MASH hepatocytes.
    Liver Cancer Collaborative
      Hepatocellular carcinoma (HCC) originates from differentiated hepatocytes undergoing compensatory proliferation in livers damaged by viruses or metabolic-dysfunction-associated steatohepatitis (MASH)1. While increasing HCC risk2, MASH triggers p53-dependent hepatocyte senescence3, which we found to parallel hypernutrition-induced DNA breaks. How this tumour-suppressive response is bypassed to license oncogenic mutagenesis and enable HCC evolution was previously unclear. Here we identified the gluconeogenic enzyme fructose-1,6-bisphosphatase 1 (FBP1) as a p53 target that is elevated in senescent-like MASH hepatocytes but suppressed through promoter hypermethylation and proteasomal degradation in most human HCCs. FBP1 first declines in metabolically stressed premalignant disease-associated hepatocytes and HCC progenitor cells4,5, paralleling the protumorigenic activation of AKT and NRF2. By accelerating FBP1 and p53 degradation, AKT and NRF2 enhance the proliferation and metabolic activity of previously senescent HCC progenitors. The senescence-reversing and proliferation-supportive NRF2-FBP1-AKT-p53 metabolic switch, operative in mice and humans, also enhances the accumulation of DNA-damage-induced somatic mutations needed for MASH-to-HCC progression.
    DOI:  https://doi.org/10.1038/s41586-024-08317-9
  3. Nat Commun. 2025 Jan 02. 16(1): 319
    Spatial transcriptomics of healthy and fibrotic human liver at single-cell resolution.
    Brianna R Watson, Biplab Paul, Raza Ur Rahman, Liat Amir-Zilberstein, Åsa Segerstolpe, Eliana T Epstein, Shane Murphy, Ludwig Geistlinger, Tyrone Lee, Angela Shih, Jacques Deguine, Ramnik J Xavier, Jeffrey R Moffitt, Alan C Mullen.
      Single-cell RNA sequencing (scRNA-seq) has advanced our understanding of cell types and their heterogeneity within the human liver, but the spatial organization at single-cell resolution has not yet been described. Here we apply multiplexed error robust fluorescent in situ hybridization (MERFISH) to map the zonal distribution of hepatocytes, spatially resolve subsets of macrophage and mesenchymal populations, and investigate the relationship between hepatocyte ploidy and gene expression within the healthy human liver. Integrating spatial information from MERFISH with the more complete transcriptome produced by single-nucleus RNA sequencing (snRNA-seq), also reveals zonally enriched receptor-ligand interactions. Finally, MERFISH and snRNA-seq analysis of fibrotic liver samples identify two hepatocyte populations that expand with injury and do not have clear zonal distributions. Together these spatial maps of the healthy and fibrotic liver provide a deeper understanding of the cellular and spatial remodeling that drives disease which, in turn, could provide new avenues for intervention and further study.
    DOI:  https://doi.org/10.1038/s41467-024-55325-4
  4. Nat Immunol. 2025 Jan;26(1): 3
    Latent HIV-1 induction.
    Paula Jauregui.
      
    DOI:  https://doi.org/10.1038/s41590-024-02055-w
  5. Nat Immunol. 2025 Jan;26(1): 13-14
    Innate immune barrier against oncogenic transformation.
      
    DOI:  https://doi.org/10.1038/s41590-024-02043-0
  6. Nat Immunol. 2025 Jan;26(1): 15-16
    Past interactions of T cells with antigens shape CAR T cell responses.
      
    DOI:  https://doi.org/10.1038/s41590-024-02048-9
  7. Nat Commun. 2024 Dec 30. 15(1): 10900
    Fast and sensitive multivalent spatial pattern-recognition for circular RNA detection.
    Zhixin Zhou, Bing Han, Yu Wang, Nina Lin, Zhongqiu Zhou, Yuan Zhang, Ying Bai, Ling Shen, Yanfei Shen, Yuanjian Zhang, Honghong Yao.
      While circular RNAs (circRNAs) exhibit lower abundance compared to corresponding linear RNAs, they demonstrate potent biological functions. Nevertheless, challenges arise from the low concentration and distinctive structural features of circRNAs, rendering existing methods operationally intricate and less sensitive. Here, we engineer an intelligent tetrahedral DNA framework (TDF) possessing precise spatial pattern-recognition properties with exceptional sensing speed and sensitivity for circRNAs. The signal output of TDF sensor occurs only when multivalent spatial pattern-recognition of a circRNA in unamplified samples. Using this sensor, we visualize the real-time response of endogenous circRNA expression in vitro neuronal cells and in vivo brain between pre-stroke and post-stroke male mice, identify the patients with acute ischemic stroke in clinical samples, as well as track the delivery of circRNA in photochromic stroked animal model. Thus, the TDF sensor provides a fast and sensitive tool for the detection of circRNA abundance in both physiological and pathophysiological conditions.
    DOI:  https://doi.org/10.1038/s41467-024-55364-x
  8. Nat Cell Biol. 2025 Jan 02.
    AMPK-regulated glycerol excretion maintains metabolic crosstalk between reductive and energetic stress.
    Xuewei Zhai, Ronghui Yang, Qiaoyun Chu, Zihao Guo, Pengjiao Hou, Xuexue Li, Changsen Bai, Ziwen Lu, Luxin Qiao, Yanxia Fu, Jing Niu, Binghui Li.
      Glucose metabolism has been studied extensively, but the role of glucose-derived excretory glycerol remains unclear. Here we show that hypoxia induces NADH accumulation to promote glycerol excretion and this pathway consumes NADH continuously, thus attenuating its accumulation and reductive stress. Aldolase B accounts for glycerol biosynthesis by forming a complex with glycerol 3-phosphate dehydrogenases GPD1 and GPD1L. Blocking GPD1, GPD1L or glycerol 3-phosphate phosphatase exacerbates reductive stress and suppresses cell proliferation under hypoxia and tumour growth in vivo. Overexpression of these enzymes increases glycerol excretion but still reduces cell viability under hypoxia and tumour proliferation due to energy stress. AMPK inactivates aldolase B to mitigate glycerol synthesis that dissipates ATP, alleviating NADH accumulation-induced energy crisis. Therefore, glycerol biosynthesis/excretion regulates the trade-off between reductive stress and energy stress. Moreover, this mode of regulation seems to be prevalent in reductive stress-driven transformations, enhancing our understanding of the metabolic complexity and guiding tumour treatment.
    DOI:  https://doi.org/10.1038/s41556-024-01549-x
  9. Cell. 2024 Dec 30. pii: S0092-8674(24)01346-1. [Epub ahead of print]
    DNA end sensing and cleavage by the Shedu anti-phage defense system.
    Luuk Loeff, Alexander Walter, Gian Tizio Rosalen, Martin Jinek.
      The detection of molecular patterns associated with invading pathogens is a hallmark of innate immune systems. Prokaryotes deploy sophisticated host defense mechanisms in innate anti-phage immunity. Shedu is a single-component defense system comprising a putative nuclease SduA. Here, we report cryoelectron microscopy (cryo-EM) structures of apo- and double-stranded DNA (dsDNA)-bound tetrameric SduA assemblies, revealing that the N-terminal domains of SduA form a clamp that recognizes free DNA ends. End binding positions the DNA over the PD-(D/E)XK nuclease domain, resulting in dsDNA nicking at a fixed distance from the 5' end. The end-directed DNA nicking activity of Shedu prevents propagation of linear DNA in vivo. Finally, we show that phages escape Shedu immunity by suppressing their recombination-dependent DNA replication pathway. Taken together, these results define the antiviral mechanism of Shedu systems, underlining the paradigm that recognition of pathogen-specific nucleic acid structures is a conserved feature of innate immunity across all domains of life.
    Keywords:  DNA sensing; DUF4263; Shedu; anti-phage; genome defense; innate immunity; nuclease; pattern recognition; prokaryotic immune system
    DOI:  https://doi.org/10.1016/j.cell.2024.11.030
  10. Cell Rep. 2024 Dec 27. pii: S2211-1247(24)01449-9. [Epub ahead of print]44(1): 115098
    The T cell receptor sequence influences the likelihood of T cell memory formation.
    Kaitlyn A Lagattuta, Ayano C Kohlgruber, Nouran S Abdelfattah, Aparna Nathan, Laurie Rumker, Michael E Birnbaum, Stephen J Elledge, Soumya Raychaudhuri.
      The amino acid sequence of the T cell receptor (TCR) varies between T cells of an individual's immune system. Particular TCR residues nearly guarantee mucosal-associated invariant T (MAIT) and natural killer T (NKT) cell transcriptional fates. To define how the TCR sequence affects T cell fates, we analyze the paired αβTCR sequence and transcriptome of 961,531 single cells. We find that hydrophobic complementarity-determining region (CDR)3 residues promote regulatory T cell fates in both the CD8 and CD4 lineages. Most strikingly, we find a set of TCR sequence features that promote the T cell transition from naive to memory. We quantify the extent of these features through our TCR scoring function "TCR-mem." Using TCR transduction experiments, we demonstrate that increased TCR-mem promotes T cell activation, even among T cells that recognize the same antigen. Our results reveal a common set of TCR sequence features that enable T cell activation and immunological memory.
    Keywords:  CP: Immunology; T-cells; TCR; activation; immunology; memory; transcriptomics
    DOI:  https://doi.org/10.1016/j.celrep.2024.115098
  11. Cell. 2024 Dec 26. pii: S0092-8674(24)01344-8. [Epub ahead of print]
    Global organelle profiling reveals subcellular localization and remodeling at proteome scale.
    Marco Y Hein, Duo Peng, Verina Todorova, Frank McCarthy, Kibeom Kim, Chad Liu, Laura Savy, Camille Januel, Rodrigo Baltazar-Nunez, Madhurya Sekhar, Shivanshi Vaid, Sophie Bax, Madhuri Vangipuram, James Burgess, Leila Njoya, Eileen Wang, Ivan E Ivanov, Janie R Byrum, Soorya Pradeep, Carlos G Gonzalez, Yttria Aniseia, Joseph S Creery, Aidan H McMorrow, Sara Sunshine, Serena Yeung-Levy, Brian C DeFelice, Shalin B Mehta, Daniel N Itzhak, Joshua E Elias, Manuel D Leonetti.
      Defining the subcellular distribution of all human proteins and their remodeling across cellular states remains a central goal in cell biology. Here, we present a high-resolution strategy to map subcellular organization using organelle immunocapture coupled to mass spectrometry. We apply this workflow to a cell-wide collection of membranous and membraneless compartments. A graph-based analysis assigns the subcellular localization of over 7,600 proteins, defines spatial networks, and uncovers interconnections between cellular compartments. Our approach can be deployed to comprehensively profile proteome remodeling during cellular perturbation. By characterizing the cellular landscape following HCoV-OC43 viral infection, we discover that many proteins are regulated by changes in their spatial distribution rather than by changes in abundance. Our results establish that proteome-wide analysis of subcellular remodeling provides key insights for elucidating cellular responses, uncovering an essential role for ferroptosis in OC43 infection. Our dataset can be explored at organelles.czbiohub.org.
    Keywords:  CRISPR; HCoV-OC43 coronavirus; cell biology; ferroptosis; k-NN graph; mass spectrometry; native organelle IP; protein localization; spatial proteomics; subcellular remodeling; viral infection
    DOI:  https://doi.org/10.1016/j.cell.2024.11.028
  12. Nat Commun. 2024 Dec 30. 15(1): 10838
    Mammalian SLC39A13 promotes ER/Golgi iron transport and iron homeostasis in multiple compartments.
    Huihui Li, Yanmei Cui, Yule Hu, Mengran Zhao, Kuanyu Li, Xiaoyun Pang, Fei Sun, Bing Zhou.
      Iron is a potent biochemical, and accurate homeostatic control is orchestrated by a network of interacting players at multiple levels. Although our understanding of organismal iron homeostasis has advanced, intracellular iron homeostasis is poorly understood, including coordination between organelles and iron export into the ER/Golgi. Here, we show that SLC39A13 (ZIP13), previously identified as a zinc transporter, promotes intracellular iron transport and reduces intracellular iron levels. ZIP13 loss causes an iron deficiency in the ER/Golgi and other intracellular compartments, such as lysosomes and mitochondria, as well as elevating iron in the cytosol. ZIP13 overexpression has the opposite effect, increasing iron in organellar compartments. We suggest that ZIP13 gatekeeps an iron trafficking route that shunts iron from the cytosol to the ER/Golgi hub. Zip13-knockout male mice have iron deposition in several tissues. These data demonstrate that mammalian ZIP13 is crucial for iron homeostasis and suggest a potential iron transport function.
    DOI:  https://doi.org/10.1038/s41467-024-55149-2
  13. Nature. 2025 Jan 01.
    Paradoxical link between senescent cell state and liver cancer resolved.
      
    Keywords:  Cancer; Cell biology
    DOI:  https://doi.org/10.1038/d41586-024-04137-z
  14. Nat Med. 2025 Jan 02.
    Genetic insights into global heterogeneity of type 2 diabetes.
    Miriam S Udler.
      
    DOI:  https://doi.org/10.1038/s41591-024-03413-9
  15. Nat Commun. 2024 Dec 30. 15(1): 10782
    Chk2 sustains PLK1 activity in mitosis to ensure proper chromosome segregation.
    Elizabeth M Black, Carlos Andrés Ramírez Parrado, Isabelle Trier, Wenxue Li, Yoon Ki Joo, Jennifer Pichurin, Yansheng Liu, Lilian Kabeche.
      Polo-like kinase 1 (PLK1) protects against genome instability by ensuring timely and accurate mitotic cell division, and its activity is tightly regulated throughout the cell cycle. Although the pathways that initially activate PLK1 in G2 are well-characterized, the factors that directly regulate mitotic PLK1 remain poorly understood. Here, we identify that human PLK1 activity is sustained by the DNA damage response kinase Checkpoint kinase 2 (Chk2) in mitosis. Chk2 directly phosphorylates PLK1 T210, a residue on its T-loop whose phosphorylation is essential for full PLK1 kinase activity. Loss of Chk2-dependent PLK1 activity causes increased mitotic errors, including chromosome misalignment, chromosome missegregation, and cytokinetic defects. Moreover, Chk2 deficiency increases sensitivity to PLK1 inhibitors, suggesting that Chk2 status may be an informative biomarker for PLK1 inhibitor efficacy. This work demonstrates that Chk2 sustains mitotic PLK1 activity and protects genome stability through discrete functions in interphase DNA damage repair and mitotic chromosome segregation.
    DOI:  https://doi.org/10.1038/s41467-024-54922-7
  16. Nat Immunol. 2025 Jan;26(1): 7-8
    Platelet partnerships and lasting memories.
    Petter Brodin.
      
    DOI:  https://doi.org/10.1038/s41590-024-02040-3
  17. Nat Commun. 2025 Jan 02. 16(1): 95
    diaTracer enables spectrum-centric analysis of diaPASEF proteomics data.
    Kai Li, Guo Ci Teo, Kevin L Yang, Fengchao Yu, Alexey I Nesvizhskii.
      Data-independent acquisition has become a widely used strategy for peptide and protein quantification in liquid chromatography-tandem mass spectrometry-based proteomics studies. The integration of ion mobility separation into data-independent acquisition analysis, such as the diaPASEF technology available on Bruker's timsTOF platform, further improves the quantification accuracy and protein depth achievable using data-independent acquisition. We introduce diaTracer, a spectrum-centric computational tool optimized for diaPASEF data. diaTracer performs three-dimensional (mass to charge ratio, retention time, ion mobility) peak tracing and feature detection to generate precursor-resolved "pseudo-tandem mass spectra", facilitating direct ("spectral-library free") peptide identification and quantification from diaPASEF data. diaTracer is available as a stand-alone tool and is fully integrated into the widely used FragPipe computational platform. We demonstrate the performance of diaTracer and FragPipe using diaPASEF data from triple-negative breast cancer, cerebrospinal fluid, and plasma samples, data from phosphoproteomics and human leukocyte antigens immunopeptidomics experiments, and low-input data from a spatial proteomics study. We also show that diaTracer enables unrestricted identification of post-translational modifications from diaPASEF data using open/mass-offset searches.
    DOI:  https://doi.org/10.1038/s41467-024-55448-8
  18. Nature. 2025 Jan 01.
    Monoallelic expression can govern penetrance of inborn errors of immunity.
    O'Jay Stewart, Conor Gruber, Haley E Randolph, Roosheel Patel, Meredith Ramba, Enrica Calzoni, Lei Haley Huang, Jay Levy, Sofija Buta, Angelica Lee, Christos Sazeides, Zoe Prue, David P Hoytema van Konijnenburg, Ivan K Chinn, Luis A Pedroza, James R Lupski, Erica G Schmitt, Megan A Cooper, Anne Puel, Xiao Peng, Stéphanie Boisson-Dupuis, Jacinta Bustamante, Satoshi Okada, Marta Martin-Fernandez, Jordan S Orange, Jean-Laurent Casanova, Joshua D Milner, Dusan Bogunovic.
      Inborn errors of immunity (IEIs) are genetic disorders that underlie susceptibility to infection, autoimmunity, autoinflammation, allergy and/or malignancy1. Incomplete penetrance is common among IEIs despite their monogenic basis2. Here we investigate the contribution of autosomal random monoallelic expression (aRMAE), a somatic commitment to the expression of one allele3,4, to phenotypic variability observed in families with IEIs. Using a clonal primary T cell system to assess aRMAE status of genes in healthy individuals, we find that 4.30% of IEI genes and 5.20% of all genes undergo aRMAE. Perturbing H3K27me3 and DNA methylation alters allele expression commitment, in support of two proposed mechanisms5,6 for the regulation of aRMAE. We tested peripheral blood mononuclear cells from individuals with IEIs with shared genetic lesions but discordant clinical phenotypes for aRMAE. Among two relatives who were heterozygous for a mutation in PLCG2 (delEx19), an antibody deficiency phenotype corresponds to selective mutant allele expression in B cells. By contrast, among relatives who were heterozygous for a mutation in JAK1 (c.2099G>A; p.S700N), the unaffected carrier T cells predominantly expressed the wild-type JAK1 allele, whereas the affected carrier T cells exhibited biallelic expression. Allelic expression bias was also documented in phenotypically discordant family members with mutations in STAT1 and CARD11. This study highlights the importance of considering both the genotype and the 'transcriptotype' in analyses of the penetrance and expressivity of monogenic disorders.
    DOI:  https://doi.org/10.1038/s41586-024-08346-4
  19. Nat Commun. 2024 Dec 30. 15(1): 10747
    NET formation-mediated in situ protein delivery to the inflamed central nervous system.
    Yina Wu, Jinwon Park, Quoc-Viet Le, Junho Byun, Jaehyun Choi, Enzhen Xu, Jaiwoo Lee, Yu-Kyoung Oh.
      Delivering protein drugs to the central nervous system (CNS) is challenging due to the blood-brain and blood-spinal cord barrier. Here we show that neutrophils, which naturally migrate through these barriers to inflamed CNS sites and release neutrophil extracellular traps (NETs), can be leveraged for therapeutic delivery. Tannic acid nanoparticles tethered with anti-Ly6G antibody and interferon-β (aLy6G-IFNβ@TLP) are constructed for targeted neutrophil delivery. These nanoparticles protect interferon-β from reactive oxygen species and preferentially accumulate in neutrophils over other immune cells. Upon encountering inflammation, neutrophils release the nanoparticles during NET formation. In the female mouse model of experimental autoimmune encephalomyelitis, intravenous administration of aLy6G-IFNβ@TLP reduce disease progression and restore motor function. Although this study focuses on IFNβ and autoimmune encephalomyelitis, the concept of hitchhiking neutrophils for CNS delivery and employing NET formation for inflamed site-specific nanoparticle release can be further applied for delivery of other protein drugs in the treatment of neurodegenerative diseases.
    DOI:  https://doi.org/10.1038/s41467-024-54817-7
  20. Nat Commun. 2024 Dec 30. 15(1): 10736
    Integrated multi-omics profiling reveals neutrophil extracellular traps potentiate Aortic dissection progression.
    Yu-Fei Zhao, Zi-Ang Zuo, Zhe-Yun Li, Ye Yuan, Shi-Chai Hong, Wei-Guo Fu, Bin Zhou, Li-Xin Wang.
      Adverse aortic remodeling increases the risk of aorta-related adverse events (AAEs) after thoracic endovascular aortic repair (TEVAR) and affects the overall prognosis of aortic dissection (AD). It is imperative to delve into the exploration of prognostic indicators to streamline the identification of individuals at elevated risk for postoperative AAEs, and therapeutic targets to optimize the efficacy of TEVAR for patients with AD. Here, we perform proteomic and single-cell transcriptomic analyses of peripheral blood and aortic lesions, respectively, from patients with AD and healthy subjects. The integrated multi-omics profiling identifies that highly phenotype-associated macrophages orchestrate neutrophil extracellular traps (NETs) through CXCL3/CXCR2 axis, thereby promoting the development of AD. Increased NETs formation is a defining feature of systemic immunity and aortic microenvironment of AD. Inhibiting NETs formation through the blockade of citrullinated histone H3 or CXCL3/CXCR2 axis ameliorates the progression and rupture of aortic dissection in male mice. The plasma level of citrullinated histone H3 predicts AAEs following endovascular therapy, facilitating the risk stratification and prognostic evaluation for patients with AD.
    DOI:  https://doi.org/10.1038/s41467-024-55038-8
  21. Nat Commun. 2024 Dec 30. 15(1): 10919
    The chromatin remodeling factor OsINO80 promotes H3K27me3 and H3K9me2 deposition and maintains TE silencing in rice.
    Kangxi Du, Jiabing Wu, Jiachen Wang, Wenhao Xie, Liufan Yin, Xiang Li, Chao Li, Aiwu Dong.
      The INO80 chromatin remodeling complex plays a critical role in shaping the dynamic chromatin environment. The diverse functions of the evolutionarily conserved INO80 complex have been widely reported. However, the role of INO80 in modulating the histone variant H2A.Z is controversial. Moreover, whether INO80 helps regulate heterochromatin remains unknown. Here, we characterize the regulatory effects of OsINO80 on protein-coding genes and transposable elements (TEs) in rice. Upon OsINO80 overexpression in rice, we found three types of OsINO80-occupied regions with different chromatin signatures: type I (enriched with H2A.Z), type II (enriched with H3K9me2), and type III (deficient in H2A.Z/H3K9me2). Loss of OsINO80 results in a decrease in H3K27me3, but not H2A.Z, at type I regions as well as a decrease in H3K9me2 at type II regions, which correlates with TE activation and transposition. Our findings reveal that OsINO80 facilitates H3K27me3 establishment, promotes H3K9me2 deposition, and maintains TE silencing.
    DOI:  https://doi.org/10.1038/s41467-024-55387-4
  22. Nat Commun. 2025 Jan 02. 16(1): 311
    Mms22-Rtt107 axis attenuates the DNA damage checkpoint and the stability of the Rad9 checkpoint mediator.
    Bingbing Wan, Danying Guan, Shibai Li, Tzippora Chwat-Edelstein, Xiaolan Zhao.
      The DNA damage checkpoint is a highly conserved signaling pathway induced by genotoxin exposure or endogenous genome stress. It alters many cellular processes such as arresting the cell cycle progression and increasing DNA repair capacities. However, cells can downregulate the checkpoint after prolonged stress exposure to allow continued growth and alternative repair. Strategies that can dampen the DNA damage checkpoint are not well understood. Here, we report that budding yeast employs a pathway composed of the scaffold protein Rtt107, its binding partner Mms22, and an Mms22-associated ubiquitin ligase complex to downregulate the DNA damage checkpoint. Mechanistically, this pathway promotes the proteasomal degradation of a key checkpoint factor, Rad9. Furthermore, Rtt107 binding to Mms22 helps to enrich the ubiquitin ligase complex on chromatin for targeting the chromatin-bound form of Rad9. Finally, we provide evidence that the Rtt107-Mms22 axis operates in parallel with the Rtt107-Slx4 axis, which displaces Rad9 from chromatin. We thus propose that Rtt107 enables a bifurcated "anti-Rad9" strategy to optimally downregulate the DNA damage checkpoint.
    DOI:  https://doi.org/10.1038/s41467-024-54624-0
  23. Nat Commun. 2024 Dec 30. 15(1): 10871
    The Cryo-EM structure of human CD163 bound to haptoglobin-hemoglobin reveals molecular mechanisms of hemoglobin scavenging.
    Anders Etzerodt, Jakob Hauge Mikkelsen, Morten Torvund-Jensen, Dorle Hennig, Thomas Boesen, Jonas Heilskov Graversen, Søren Kragh Moestrup, Justin M Kollman, Christian Brix Folsted Andersen.
      CD163, a macrophage-specific receptor, plays a critical role in scavenging hemoglobin released during hemolysis, protecting against oxidative effects of heme iron. In the bloodstream, hemoglobin is bound by haptoglobin, leading to its immediate endocytosis by CD163. While haptoglobin's structure and function are well understood, CD163's structure and its interaction with the haptoglobin-hemoglobin complex have remained elusive. Here, we present the cryo-electron microscopy structure of the entire extracellular domain of human CD163 in complex with haptoglobin-hemoglobin. The structure reveals that CD163 assembles into trimers (and to some extent dimers), binding haptoglobin-hemoglobin in their center. Key acidic residues in CD163 interact with lysine residues from both haptoglobin and hemoglobin. Calcium-binding sites located near the haptoglobin-hemoglobin interface in CD163 provide explanation for the calcium dependence of the interaction. Furthermore, we show that the interaction facilitating CD163 oligomerization mimics ligand binding and is also calcium dependent. This structural insight into CD163 advances our understanding of its role in hemoglobin scavenging as well as its broader relevance to structurally related scavenger receptors.
    DOI:  https://doi.org/10.1038/s41467-024-55171-4
  24. Nat Commun. 2025 Jan 02. 16(1): 300
    OSP-1 protects neurons from autophagic cell death induced by acute oxidative stress.
    Alessandra Donato, Fiona K Ritchie, Lachlan Lu, Mehershad Wadia, Ramon Martinez-Marmol, Eva Kaulich, Kornraviya Sankorrakul, Hang Lu, Sean Coakley, Elizabeth J Coulson, Massimo A Hilliard.
      Oxidative stress, caused by the accumulation of reactive oxygen species (ROS), is a pathological factor in several incurable neurodegenerative conditions as well as in stroke. However, our knowledge of the genetic elements that can be manipulated to protect neurons from oxidative stress-induced cell death is still very limited. Here, using Caenorhabditis elegans as a model system, combined with the optogenetic tool KillerRed to spatially and temporally control ROS generation, we identify a previously uncharacterized gene, oxidative stress protective 1 (osp-1), that protects C. elegans neurons from oxidative damage. Using rodent and human cell cultures, we also show that the protective effect of OSP-1 extends to mammalian cells. Moreover, we demonstrate that OSP-1 functions in a strictly cell-autonomous fashion, and that it localizes to the endoplasmic reticulum (ER) where it has an ER-remodeling function. Finally, we present evidence suggesting that OSP-1 may exert its neuroprotective function by influencing autophagy. Our results point to a potential role of OSP-1 in modulating autophagy, and suggest that overactivation of this cellular process could contribute to neuronal death triggered by oxidative damage.
    DOI:  https://doi.org/10.1038/s41467-024-55105-0
  25. Nat Commun. 2024 Dec 30. 15(1): 10749
    Brainstem BDNF neurons are downstream of GFRAL/GLP1R signalling.
    Claire H Feetham, Valeria Collabolletta, Amy A Worth, Rosemary Shoop, Sam Groom, Court Harding, Mehdi Boutagouga Boudjadja, Tamer Coskun, Paul J Emmerson, Giuseppe D'Agostino, Simon M Luckman.
      Growth differentiation factor 15, GDF15, and glucagon-like peptide-1 (GLP-1) analogues act through brainstem neurons that co-localise their receptors, GDNF-family receptor α-like (GFRAL) and GLP1R, to reduce food intake and body weight. However, their use as clinical treatments is partially hampered since both can also induce sickness-like behaviours, including aversion, that are mediated through a well-characterised pathway via the exterolateral parabrachial nucleus. Here, in mice, we describe a separate pathway downstream of GFRAL/GLP1R neurons that involves a distinct population of brain-derived neurotrophic factor (BDNF) cells in the medial nucleus of the tractus solitarius. Thus, BDNFmNTS neurons are required for the weight-reducing actions of both GDF15 and the GLP1RA, Exendin-4. Moreover, acute activation of BDNFmNTS neurons is sufficient to reduce food intake and drive fatty acid oxidation and might provide a route for longer-term weight loss.
    DOI:  https://doi.org/10.1038/s41467-024-54367-y
  26. Nat Commun. 2024 Dec 30. 15(1): 10819
    A high-protein diet-responsive gut hormone regulates behavioral and metabolic optimization in Drosophila melanogaster.
    Yuto Yoshinari, Takashi Nishimura, Taishi Yoshii, Shu Kondo, Hiromu Tanimoto, Tomoe Kobayashi, Makoto Matsuyama, Ryusuke Niwa.
      Protein is essential for all living organisms; however, excessive protein intake can have adverse effects, such as hyperammonemia. Although mechanisms responding to protein deficiency are well-studied, there is a significant gap in our understanding of how organisms adaptively suppress excessive protein intake. In the present study, utilizing the fruit fly, Drosophila melanogaster, we discover that the peptide hormone CCHamide1 (CCHa1), secreted by enteroendocrine cells in response to a high-protein diet (HPD), is vital for suppressing overconsumption of protein. Gut-derived CCHa1 is received by a small subset of enteric neurons that produce short neuropeptide F, thereby modulating protein-specific satiety. Importantly, impairment of the CCHa1-mediated gut-enteric neuronal axis results in ammonia accumulation and a shortened lifespan under HPD conditions. Collectively, our findings unravel the crosstalk of gut hormone and neuronal pathways that orchestrate physiological responses to prevent and adapt to dietary protein overload.
    DOI:  https://doi.org/10.1038/s41467-024-55050-y
  27. Nat Commun. 2024 Dec 30. 15(1): 10788
    Alcohol-induced gut microbial reorganization and associated overproduction of phenylacetylglutamine promotes cardiovascular disease.
    Zhen Li, Min Gu, Aline Zaparte, Xiaoming Fu, Kala Mahen, Marko Mrdjen, Xinmin S Li, Zhihong Yang, Jing Ma, Themis Thoudam, Kristina Chandler, Maggie Hesler, Laura Heathers, Kiersten Gorse, Thanh Trung Van, David Wong, Aaron M Gibson, Zeneng Wang, Christopher M Taylor, Pearl Quijada, Catherine A Makarewich, Stanley L Hazen, Suthat Liangpunsakul, J Mark Brown, David J Lefer, David A Welsh, Thomas E Sharp.
      The mechanism(s) underlying gut microbial metabolite (GMM) contribution towards alcohol-mediated cardiovascular disease (CVD) is unknown. Herein we observe elevation in circulating phenylacetylglutamine (PAGln), a known CVD-associated GMM, in individuals living with alcohol use disorder. In a male murine binge-on-chronic alcohol model, we confirm gut microbial reorganization, elevation in PAGln levels, and the presence of cardiovascular pathophysiology. Fecal microbiota transplantation from pair-/alcohol-fed mice into naïve male mice demonstrates the transmissibility of PAGln production and the CVD phenotype. Independent of alcohol exposure, pharmacological-mediated increases in PAGln elicits direct cardiac and vascular dysfunction. PAGln induced hypercontractility and altered calcium cycling in isolated cardiomyocytes providing evidence of improper relaxation which corresponds to elevated filling pressures observed in vivo. Furthermore, PAGln directly induces vascular endothelial cell activation through induction of oxidative stress leading to endothelial cell dysfunction. We thus reveal that the alcohol-induced microbial reorganization and resultant GMM elevation, specifically PAGln, directly contributes to CVD.
    DOI:  https://doi.org/10.1038/s41467-024-55084-2
  28. Nat Commun. 2024 Dec 30. 15(1): 10784
    Anti-CTLA4 treatment reduces lymphedema risk potentially through a systemic expansion of the FOXP3+ Treg population.
    Stefan Wolf, Matiar Madanchi, Patrick Turko, Maija Hollmén, Sonia Tugues, Julia von Atzigen, Pietro Giovanoli, Reinhard Dummer, Nicole Lindenblatt, Cornelia Halin, Michael Detmar, Mitchell Levesque, Epameinondas Gousopoulos.
      Secondary lymphedema is a common sequel of oncologic surgery and presents a global health burden still lacking pharmacological treatment. The infiltration of the lymphedematous extremities with CD4+T cells influences lymphedema onset and emerges as a promising therapy target. Here, we show that the modulation of CD4+FOXP3+CD25+regulatory T (Treg) cells upon anti-CTLA4 treatment protects against lymphedema development in patients with melanoma and in a mouse lymphedema model. A retrospective evaluation of a melanoma patient registry reveals that anti-CTLA4 reduces lymphedema risk; in parallel, anti-CTLA4 reduces edema and improves lymphatic function in a mouse-tail lymphedema model. This protective effect of anti-CTLA4 correlates with a systemic expansion of Tregs, both in the animal model and in patients with melanoma. Our data thus show that anti-CTLA4 with its lymphedema-protective and anti-tumor properties is a promising candidate for more diverse application in the clinics.
    DOI:  https://doi.org/10.1038/s41467-024-55002-6
  29. Sci Transl Med. 2025 Jan;17(779): eadi6148
    G6PC2 controls glucagon secretion by defining the set point for glucose in pancreatic α cells.
    Varun Bahl, Reut Rifkind, Eric Waite, Zenab Hamdan, Catherine Lee May, Elisabetta Manduchi, Benjamin F Voight, Michelle Y Y Lee, Mark Tigue, Nicholas Manuto, Benjamin Glaser, Dana Avrahami, Klaus H Kaestner.
      Elevated glucagon concentrations have been reported in patients with type 2 diabetes (T2D). A critical role for α cell-intrinsic mechanisms in regulating glucagon secretion was previously established through genetic manipulation of the glycolytic enzyme glucokinase (GCK) in mice. Genetic variation at the glucose-6-phosphatase catalytic subunit 2 (G6PC2) locus, encoding an enzyme that opposes GCK, has been reproducibly associated with fasting blood glucose and hemoglobin A1c. Here, we found that trait-associated variants in the G6PC2 promoter are located in open chromatin not just in β but also in α cells and documented allele-specific G6PC2 expression of linked variants in human α cells. Using α cell-specific gene ablation of G6pc2 in mice, we showed that this gene plays a critical role in controlling glucose suppression of amino acid-stimulated glucagon secretion independent of alterations in insulin output, islet hormone content, or islet morphology, findings that we confirmed in primary human α cells. Collectively, our data demonstrate that G6PC2 affects glycemic control via its action in α cells and possibly suggest that G6PC2 inhibitors might help control blood glucose through a bihormonal mechanism.
    DOI:  https://doi.org/10.1126/scitranslmed.adi6148
  30. Nat Commun. 2025 Jan 02. 16(1): 27
    Cooperative integration of spatially resolved multi-omics data with COSMOS.
    Yuansheng Zhou, Xue Xiao, Lei Dong, Chen Tang, Guanghua Xiao, Lin Xu.
      Recent advancements in biological technologies have enabled the measurement of spatially resolved multi-omics data, yet computational algorithms for this purpose are scarce. Existing tools target either single omics or lack spatial integration. We generate a graph neural network algorithm named COSMOS to address this gap and demonstrated the superior performance of COSMOS in domain segmentation, visualization, and spatiotemporal map for spatially resolved multi-omics data integration tasks.
    DOI:  https://doi.org/10.1038/s41467-024-55204-y
  31. Nat Cell Biol. 2025 Jan 02.
    Nuclear speckles regulate functional programs in cancer.
    Katherine A Alexander, Ruofan Yu, Nicolas Skuli, Nathan J Coffey, Son Nguyen, Christine L Faunce, Hua Huang, Ian P Dardani, Austin L Good, Joan Lim, Catherine Y Li, Nicholas Biddle, Eric F Joyce, Arjun Raj, Daniel Lee, Brian Keith, M Celeste Simon, Shelley L Berger.
      Nuclear speckles are dynamic nuclear bodies characterized by high concentrations of factors involved in RNA production. Although the contents of speckles suggest multifaceted roles in gene regulation, their biological functions are unclear. Here we investigate speckle variation in human cancer, finding two main signatures. One speckle signature was similar to healthy adjacent tissues, whereas the other was dissimilar, and considered an aberrant cancer speckle state. Aberrant speckles show altered positioning within the nucleus, higher levels of the TREX RNA export complex and correlate with poorer patient outcomes in clear cell renal cell carcinoma (ccRCC), a cancer typified by hyperactivation of the HIF-2α transcription factor. We demonstrate that HIF-2α promotes physical association of certain target genes with speckles depending on HIF-2α protein speckle-targeting motifs, defined in this study. We identify homologous speckle-targeting motifs within many transcription factors, suggesting that DNA-speckle targeting may be a general gene regulatory mechanism. Integrating functional, genomic and imaging studies, we show that HIF-2α gene regulatory programs are impacted by speckle state and by abrogation of HIF-2α-driven speckle targeting. These findings suggest that, in ccRCC, a key biological function of nuclear speckles is to modulate expression of select HIF-2α-regulated target genes that, in turn, influence patient outcomes. Beyond ccRCC, tumour speckle states broadly correlate with altered functional pathways and expression of speckle-associated gene neighbourhoods, exposing a general link between nuclear speckles and gene expression dysregulation in human cancer.
    DOI:  https://doi.org/10.1038/s41556-024-01570-0
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