bims-nimamd Biomed News
on Neuroimmunity and neuroinflammation in ageing and metabolic disease
Issue of 2024‒08‒18
thirty-six papers selected by
Fawaz Alzaïd, Sorbonne Université
  1. Lymphotoxin limits Foxp3+ regulatory T cell development from Foxp3lo precursors via IL-4 signaling.
  2. SRF SUMOylation modulates smooth muscle phenotypic switch and vascular remodeling.
  3. ZFP318 fuels memory B cells for success.
  4. Engineered probiotic Escherichia coli elicits immediate and long-term protection against influenza A virus in mice.
  5. Exploring how APOE ε4 increases Alzheimer's disease risk in women.
  6. How the human brain creates cognitive maps of related concepts.
  7. One-quarter of unresponsive people with brain injuries are conscious.
  8. Platelet extracellular vesicles preserve lymphatic endothelial cell integrity and enhance lymphatic vessel function.
  9. Proximity analysis of native proteomes reveals phenotypic modifiers in a mouse model of autism and related neurodevelopmental conditions.
  10. Anti-LAG-3 boosts CD8 T cell effector function.
  11. Silencing prion protein expression in the brain.
  12. Famine exposure in the womb doubles diabetes risk decades later.
  13. Structure of a fully assembled γδ T-cell antigen receptor.
  14. Liver kinase B1 (LKB1) regulates the epigenetic landscape of mouse pancreatic beta cells.
  15. Quantitative analysis of cis-regulatory elements in transcription with KAS-ATAC-seq.
  16. The effect of transient, constricted migration on neutrophil intracellular bacteria-killing capability.
  17. Macrophages dig into the obesity paradox in cancer.
  18. A homeostatic gut-to-brain insulin antagonist restrains neuronally stimulated fat loss.
  19. Two HUSH complexes connect a direct LINE to innate immunity.
  20. Brain aging patterns in a large and diverse cohort of 49,482 individuals.
  21. Posttranslationally modified self-peptides promote hypertension in mouse models.
  22. RNU4-2 variants cause neurodevelopmental disorders.
  23. SLC44A2-mediated phenotypic switch of vascular smooth muscle cells contributes to aortic aneurysm.
  24. How to win funding to talk about your science.
  25. Transporter-mediated depletion of extracellular proline directly contributes to plant pattern-triggered immunity against a bacterial pathogen.
  26. Challenging the role of a NOX4-Piezo1 axis in neutrophil bactericidal function.
  27. Mitochondrial complex I promotes kidney cancer metastasis.
  28. The molecular architecture of the nuclear basket.
  29. Inhibition of glycosphingolipid synthesis with eliglustat in combination with immune checkpoint inhibitors in advanced cancers: preclinical evidence and phase I clinical trial.
  30. ScreenDMT reveals DiHOMEs are replicably inversely associated with BMI and stimulate adipocyte calcium influx.
  31. Genetic and functional analysis of Raynaud's syndrome implicates loci in vasculature and immunity.
  32. Defective mitochondrial COX1 translation due to loss of COX14 function triggers ROS-induced inflammation in mouse liver.
  33. Protein language model enables fast and sensitive remote homolog detection.
  34. Tracing the origins of lung fibrosis.
  35. MAVS Cys508 palmitoylation promotes its aggregation on the mitochondrial outer membrane and antiviral innate immunity.
  36. ACLY and ACSS2 link nutrient-dependent chromatin accessibility to CD8 T cell effector responses.
  1. Nat Commun. 2024 Aug 14. 15(1): 6976
    Lymphotoxin limits Foxp3+ regulatory T cell development from Foxp3lo precursors via IL-4 signaling.
    Alexia Borelli, Jérémy C Santamaria, Cloé Zamit, Cécile Apert, Jessica Chevallier, Philippe Pierre, Rafael J Argüello, Lionel Spinelli, Magali Irla.
      Regulatory T cells (Treg) are critical players of immune tolerance that develop in the thymus via two distinct developmental pathways involving CD25+Foxp3- and CD25-Foxp3lo precursors. However, the mechanisms regulating the recently identified Foxp3lo precursor pathway remain unclear. Here, we find that the membrane-bound lymphotoxin α1β2 (LTα1β2) heterocomplex is upregulated during Treg development upon TCR/CD28 and IL-2 stimulation. We show that Lta expression limits the maturational development of Treg from Foxp3lo precursors by regulating their proliferation, survival, and metabolic profile. Transgenic reporter mice and transcriptomic analyses further reveal that medullary thymic epithelial cells (mTEC) constitute an unexpected source of IL-4. We demonstrate that LTα1β2-lymphotoxin β receptor-mediated interactions with mTEC limit Treg development by down-regulating IL-4 expression in mTEC. Collectively, our findings identify the lymphotoxin axis as the first inhibitory checkpoint of thymic Treg development that fine-tunes the Foxp3lo Treg precursor pathway by limiting IL-4 availability.
    DOI:  https://doi.org/10.1038/s41467-024-51164-5
  2. Nat Commun. 2024 Aug 13. 15(1): 6919
    SRF SUMOylation modulates smooth muscle phenotypic switch and vascular remodeling.
    Yue Xu, Haifeng Zhang, Yuxin Chen, Jordan S Pober, Min Zhou, Jenny Huanjiao Zhou, Wang Min.
      Serum response factor (SRF) controls gene transcription in vascular smooth muscle cells (VSMCs) and regulates VSMC phenotypic switch from a contractile to a synthetic state, which plays a key role in the pathogenesis of cardiovascular diseases (CVD). It is not known how post-translational SUMOylation regulates the SRF activity in CVD. Here we show that Senp1 deficiency in VSMCs increased SUMOylated SRF and the SRF-ELK complex, leading to augmented vascular remodeling and neointimal formation in mice. Mechanistically, SENP1 deficiency in VSMCs increases SRF SUMOylation at lysine 143, reducing SRF lysosomal localization concomitant with increased nuclear accumulation and switching a contractile phenotype-responsive SRF-myocardin complex to a synthetic phenotype-responsive SRF-ELK1 complex. SUMOylated SRF and phospho-ELK1 are increased in VSMCs from coronary arteries of CVD patients. Importantly, ELK inhibitor AZD6244 prevents the shift from SRF-myocardin to SRF-ELK complex, attenuating VSMC synthetic phenotypes and neointimal formation in Senp1-deficient mice. Therefore, targeting the SRF complex may have a therapeutic potential for the treatment of CVD.
    DOI:  https://doi.org/10.1038/s41467-024-51350-5
  3. Immunity. 2024 Aug 13. pii: S1074-7613(24)00366-2. [Epub ahead of print]57(8): 1723-1725
    ZFP318 fuels memory B cells for success.
    Fiamma Salerno, Michelle A Linterman.
      Diversity is a key feature of B cell biology-from BCR rearrangement to the heterogeneity of memory B cells. In this issue of Immunity, Wang et al. show that the zinc-finger protein ZFP318 supports mitochondrial health in certain memory B cells, thereby facilitating potent recall upon rechallenge.
    DOI:  https://doi.org/10.1016/j.immuni.2024.07.017
  4. Nat Commun. 2024 Aug 09. 15(1): 6802
    Engineered probiotic Escherichia coli elicits immediate and long-term protection against influenza A virus in mice.
    Ling Huang, Wei Tang, Lina He, Mengke Li, Xian Lin, Ao Hu, Xindi Huang, Zhouyu Wu, Zhiyong Wu, Shiyun Chen, Yangbo Hu.
      Influenza virus infection remains a major global health problem and requires a universal vaccine with broad protection against different subtypes as well as a rapid-response vaccine to provide immediate protection in the event of an epidemic outbreak. Here, we show that intranasal administration of probiotic Escherichia coli Nissle 1917 activates innate immunity in the respiratory tract and provides immediate protection against influenza virus infection within 1 day. Based on this vehicle, a recombinant strain is engineered to express and secret five tandem repeats of the extracellular domain of matrix protein 2 from different influenza virus subtypes. Intranasal vaccination with this strain induces durable humoral and mucosal responses in the respiratory tract, and provides broad protection against the lethal challenge of divergent influenza viruses in female BALB/c mice. Our findings highlight a promising delivery platform for developing mucosal vaccines that provide immediate and sustained protection against respiratory pathogens.
    DOI:  https://doi.org/10.1038/s41467-024-51182-3
  5. Nat Aging. 2024 Aug 12.
    Exploring how APOE ε4 increases Alzheimer's disease risk in women.
    George Andrew S Inglis.
      
    DOI:  https://doi.org/10.1038/s43587-024-00698-w
  6. Nature. 2024 Aug 14.
    How the human brain creates cognitive maps of related concepts.
    Mitchell Ostrow, Ila Fiete.
      
    Keywords:  Brain; Neuroscience
    DOI:  https://doi.org/10.1038/d41586-024-02433-2
  7. Nature. 2024 Aug 14.
    One-quarter of unresponsive people with brain injuries are conscious.
    Julian Nowogrodzki.
      
    Keywords:  Brain; Imaging; Medical research; Neuroscience
    DOI:  https://doi.org/10.1038/d41586-024-02614-z
  8. Commun Biol. 2024 Aug 11. 7(1): 975
    Platelet extracellular vesicles preserve lymphatic endothelial cell integrity and enhance lymphatic vessel function.
    Laurent Vachon, Gabriel Jean, Andreea Milasan, Sara Babran, Elizabeth Lacroix, Dainelys Guadarrama Bello, Louis Villeneuve, Janusz Rak, Antonio Nanci, Teodora Mihalache-Avram, Jean-Claude Tardif, Vincent Finnerty, Matthieu Ruiz, Eric Boilard, Nolwenn Tessier, Catherine Martel.
      Lymphatic vessels are essential for preventing the accumulation of harmful components within peripheral tissues, including the artery wall. Various endogenous mechanisms maintain adequate lymphatic function throughout life, with platelets being essential for preserving lymphatic vessel integrity. However, since lymph lacks platelets, their impact on the lymphatic system has long been viewed as restricted to areas where lymphatics intersect with blood vessels. Nevertheless, platelets can also exert long range effects through the release of extracellular vesicles (EVs) upon activation. We observed that platelet EVs (PEVs) are present in lymph, a compartment to which they could transfer regulatory effects of platelets. Here, we report that PEVs in lymph exhibit a distinct signature enabling them to interact with lymphatic endothelial cells (LECs). In vitro experiments show that the internalization of PEVs by LECs maintains their functional integrity. Treatment with PEVs improves lymphatic contraction capacity in atherosclerosis-prone mice. We suggest that boosting lymphatic pumping with exogenous PEVs offers a novel therapeutic approach for chronic inflammatory diseases characterized by defective lymphatics.
    DOI:  https://doi.org/10.1038/s42003-024-06675-8
  9. Nat Commun. 2024 Aug 09. 15(1): 6801
    Proximity analysis of native proteomes reveals phenotypic modifiers in a mouse model of autism and related neurodevelopmental conditions.
    Yudong Gao, Daichi Shonai, Matthew Trn, Jieqing Zhao, Erik J Soderblom, S Alexandra Garcia-Moreno, Charles A Gersbach, William C Wetsel, Geraldine Dawson, Dmitry Velmeshev, Yong-Hui Jiang, Laura G Sloofman, Joseph D Buxbaum, Scott H Soderling.
      One of the main drivers of autism spectrum disorder is risk alleles within hundreds of genes, which may interact within shared but unknown protein complexes. Here we develop a scalable genome-editing-mediated approach to target 14 high-confidence autism risk genes within the mouse brain for proximity-based endogenous proteomics, achieving the identification of high-specificity spatial proteomes. The resulting native proximity proteomes are enriched for human genes dysregulated in the brain of autistic individuals, and reveal proximity interactions between proteins from high-confidence risk genes with those of lower-confidence that may provide new avenues to prioritize genetic risk. Importantly, the datasets are enriched for shared cellular functions and genetic interactions that may underlie the condition. We test this notion by spatial proteomics and CRISPR-based regulation of expression in two autism models, demonstrating functional interactions that modulate mechanisms of their dysregulation. Together, these results reveal native proteome networks in vivo relevant to autism, providing new inroads for understanding and manipulating the cellular drivers underpinning its etiology.
    DOI:  https://doi.org/10.1038/s41467-024-51037-x
  10. Cell. 2024 Aug 08. pii: S0092-8674(24)00764-5. [Epub ahead of print]187(16): 4144-4146
    Anti-LAG-3 boosts CD8 T cell effector function.
    Courtney T Kureshi, Michael Dougan, Stephanie K Dougan.
      LAG-3 is the third immune checkpoint pathway successfully targeted for cancer therapy. Although ineffective as a monotherapy, combination of LAG-3 and PD-1 blockade improves survival from advanced melanoma. In this issue of Cell, two studies in mice and a human clinical trial provide insights on LAG-3 in immune regulation.
    DOI:  https://doi.org/10.1016/j.cell.2024.07.004
  11. Nat Genet. 2024 Aug;56(8): 1541
    Silencing prion protein expression in the brain.
    Tiago Faial.
      
    DOI:  https://doi.org/10.1038/s41588-024-01888-3
  12. Nature. 2024 Aug 08.
    Famine exposure in the womb doubles diabetes risk decades later.
    Gemma Conroy.
      
    Keywords:  Diabetes; Diseases; Nutrition
    DOI:  https://doi.org/10.1038/d41586-024-02563-7
  13. Nature. 2024 Aug 15.
    Structure of a fully assembled γδ T-cell antigen receptor.
    Benjamin S Gully, João Ferreira Fernandes, Sachith D Gunasinghe, Mai T Vuong, Yuan Lui, Michael T Rice, Liam Rashleigh, Chan-Sien Lay, Dene R Littler, Sumana Sharma, Ana Mafalda Santos, Hariprasad Venugopal, Jamie Rossjohn, Simon J Davis.
      T cells in jawed vertebrates comprise two lineages, αβ T-cells and γδ T-cells, defined by the antigen receptors they express, i.e., αβ and γδ T-cell receptors (TCRs), respectively. The two lineages have different immunological roles, requiring γδ TCRs to recognize more structurally-diverse ligands1. Nevertheless, the receptors use shared CD3 subunits to initiate signaling. Whereas the structural organization of αβ TCRs is understood2,3, the architecture of γδ TCRs is unknown. Here, we used cryogenic electron microscopy to determine the structure of a fully-assembled, MR1-reactive human Vδ3Vγ8 TCR/CD3δγε2ζ2 complex bound by anti-CD3ε antibody Fab fragments4,5. The arrangement of CD3 subunits in γδ and αβ TCRs is conserved and, although the transmembrane α-helices of the TCR-γδ and -αβ subunits differ markedly in sequence, the packing of the eight transmembrane-helix bundles is similar6. However, in contrast to the apparently rigid αβ TCR2,3,6, the γδ TCR exhibits considerable conformational heterogeneity, owing to the ligand-binding TCR-γδ subunits being tethered to the CD3 subunits by their transmembrane regions only. Reducing this conformational heterogeneity by transferring the Vδ3Vγ8 TCR variable domains to an αβ TCR enhanced receptor signaling, suggesting that γδ TCR organization reflects a compromise between efficient signaling and the ability to engage structurally-diverse ligands. Our findings reveal the remarkable structural plasticity of the TCR on evolutionary timescales, and recast it as a highly versatile receptor capable of initiating signaling as either a rigid or flexible structure.
    DOI:  https://doi.org/10.1038/s41586-024-07920-0
  14. FASEB J. 2024 Aug 31. 38(16): e23885
    Liver kinase B1 (LKB1) regulates the epigenetic landscape of mouse pancreatic beta cells.
    Nejc Haberman, Rebecca Cheung, Grazia Pizza, Nevena Cvetesic, Dorka Nagy, Hannah Maude, Lorea Blazquez, Boris Lenhard, Inês Cebola, Guy A Rutter, Aida Martinez-Sanchez.
      Liver kinase B1 (LKB1/STK11) is an important regulator of pancreatic β-cell identity and function. Elimination of Lkb1 from the β-cell results in improved glucose-stimulated insulin secretion and is accompanied by profound changes in gene expression, including the upregulation of several neuronal genes. The mechanisms through which LKB1 controls gene expression are, at present, poorly understood. Here, we explore the impact of β cell-selective deletion of Lkb1 on chromatin accessibility in mouse pancreatic islets. To characterize the role of LKB1 in the regulation of gene expression at the transcriptional level, we combine these data with a map of islet active transcription start sites and histone marks. We demonstrate that LKB1 elimination from β-cells results in widespread changes in chromatin accessibility, correlating with changes in transcript levels. Changes occurred in hundreds of promoter and enhancer regions, many of which were close to neuronal genes. We reveal that dysregulated enhancers are enriched in binding motifs for transcription factors (TFs) important for β-cell identity, such as FOXA, MAFA or RFX6, and we identify microRNAs (miRNAs) that are regulated by LKB1 at the transcriptional level. Overall, our study provides important new insights into the epigenetic mechanisms by which LKB1 regulates β-cell identity and function.
    DOI:  https://doi.org/10.1096/fj.202401078R
  15. Nat Commun. 2024 Aug 10. 15(1): 6852
    Quantitative analysis of cis-regulatory elements in transcription with KAS-ATAC-seq.
    Ruitu Lyu, Yun Gao, Tong Wu, Chang Ye, Pingluan Wang, Chuan He.
      Cis-regulatory elements (CREs) are pivotal in orchestrating gene expression throughout diverse biological systems. Accurate identification and in-depth characterization of functional CREs are crucial for decoding gene regulation networks during cellular processes. In this study, we develop Kethoxal-Assisted Single-stranded DNA Assay for Transposase-Accessible Chromatin with Sequencing (KAS-ATAC-seq) to quantitatively analyze the transcriptional activity of CREs. A main advantage of KAS-ATAC-seq lies in its precise measurement of ssDNA levels within both proximal and distal ATAC-seq peaks, enabling the identification of transcriptional regulatory sequences. This feature is particularly adept at defining Single-Stranded Transcribing Enhancers (SSTEs). SSTEs are highly enriched with nascent RNAs and specific transcription factors (TFs) binding sites that define cellular identity. Moreover, KAS-ATAC-seq provides a detailed characterization and functional implications of various SSTE subtypes. Our analysis of CREs during mouse neural differentiation demonstrates that KAS-ATAC-seq can effectively identify immediate-early activated CREs in response to retinoic acid (RA) treatment. Our findings indicate that KAS-ATAC-seq provides more precise annotation of functional CREs in transcription. Future applications of KAS-ATAC-seq would help elucidate the intricate dynamics of gene regulation in diverse biological processes.
    DOI:  https://doi.org/10.1038/s41467-024-50680-8
  16. Immunity. 2024 Aug 13. pii: S1074-7613(24)00357-1. [Epub ahead of print]57(8): 1713-1715
    The effect of transient, constricted migration on neutrophil intracellular bacteria-killing capability.
    Peng Wu, Alan Y Hsu, Ting Peng, Wenxue Zhao, Fei Liu, Zhaoran Zhang, Laxman Ghimire, Arumugam Balasubramanian, Xuemei Xie, Jiajia Li, Shin-Young Park, Fengxia Ma, Cheng Li, Hongbo R Luo.
      
    DOI:  https://doi.org/10.1016/j.immuni.2024.07.008
  17. Immunity. 2024 Aug 13. pii: S1074-7613(24)00362-5. [Epub ahead of print]57(8): 1731-1733
    Macrophages dig into the obesity paradox in cancer.
    Christopher S Nabel, Florian Gourgue, Matthew G Vander Heiden.
      Response to immune checkpoint blockade is increased in obesity-related cancers, but the mechanisms remain unclear. In a recent issue of Nature, Bader et al. report that obesity in mice induces macrophage PD-1 upregulation to promote tumor growth while potentiating immunotherapy responses.
    DOI:  https://doi.org/10.1016/j.immuni.2024.07.013
  18. Nat Commun. 2024 Aug 11. 15(1): 6869
    A homeostatic gut-to-brain insulin antagonist restrains neuronally stimulated fat loss.
    Chung-Chih Liu, Ayub Khan, Nicolas Seban, Nicole Littlejohn, Aayushi Shah, Supriya Srinivasan.
      In C. elegans mechanisms by which peripheral organs relay internal state information to the nervous system remain unknown, although strong evidence suggests that such signals do exist. Here we report the discovery of a peptide of the ancestral insulin superfamily called INS-7 that functions as an enteroendocrine peptide and is secreted from specialized cells of the intestine. INS-7 secretion is stimulated by food withdrawal, increases during fasting and acts as a bona fide gut-to-brain peptide that attenuates the release of a neuropeptide that drives fat loss in the periphery. Thus, INS-7 functions as a homeostatic signal from the intestine that gates the neuronal drive to stimulate fat loss during food shortage. Mechanistically, INS-7 functions as an antagonist at the canonical DAF-2 receptor and functions via FOXO and AMPK signaling in ASI neurons. Phylogenetic analysis suggests that INS-7 bears greater resemblance to members of the broad insulin/relaxin superfamily than to conventional mammalian insulin and IGF peptides. The discovery of an endogenous insulin antagonist secreted by specialized intestinal cells with enteroendocrine functions suggests unexpected and important properties of the intestine and its role in directing neuronal functions.
    DOI:  https://doi.org/10.1038/s41467-024-51077-3
  19. Mol Cell. 2024 Aug 08. pii: S1097-2765(24)00586-0. [Epub ahead of print]84(15): 2801-2803
    Two HUSH complexes connect a direct LINE to innate immunity.
    Geoffrey J Faulkner.
      In this issue of Molecular Cell, Danac et al.1 identify a second HUSH complex, HUSH2, that represses interferon-stimulated genes and, by competing for subunits with the canonical HUSH complex, couples LINE-1 (L1) retrotransposon transcription with immune activation.
    DOI:  https://doi.org/10.1016/j.molcel.2024.07.010
  20. Nat Med. 2024 Aug 15.
    Brain aging patterns in a large and diverse cohort of 49,482 individuals.
    Zhijian Yang, Junhao Wen, Guray Erus, Sindhuja T Govindarajan, Randa Melhem, Elizabeth Mamourian, Yuhan Cui, Dhivya Srinivasan, Ahmed Abdulkadir, Paraskevi Parmpi, Katharina Wittfeld, Hans J Grabe, Robin Bülow, Stefan Frenzel, Duygu Tosun, Murat Bilgel, Yang An, Dahyun Yi, Daniel S Marcus, Pamela LaMontagne, Tammie L S Benzinger, Susan R Heckbert, Thomas R Austin, Shari R Waldstein, Michele K Evans, Alan B Zonderman, Lenore J Launer, Aristeidis Sotiras, Mark A Espeland, Colin L Masters, Paul Maruff, Jurgen Fripp, Arthur W Toga, Sid O'Bryant, Mallar M Chakravarty, Sylvia Villeneuve, Sterling C Johnson, John C Morris, Marilyn S Albert, Kristine Yaffe, Henry Völzke, Luigi Ferrucci, R Nick Bryan, Russell T Shinohara, Yong Fan, Mohamad Habes, Paris Alexandros Lalousis, Nikolaos Koutsouleris, David A Wolk, Susan M Resnick, Haochang Shou, Ilya M Nasrallah, Christos Davatzikos.
      Brain aging process is influenced by various lifestyle, environmental and genetic factors, as well as by age-related and often coexisting pathologies. Magnetic resonance imaging and artificial intelligence methods have been instrumental in understanding neuroanatomical changes that occur during aging. Large, diverse population studies enable identifying comprehensive and representative brain change patterns resulting from distinct but overlapping pathological and biological factors, revealing intersections and heterogeneity in affected brain regions and clinical phenotypes. Herein, we leverage a state-of-the-art deep-representation learning method, Surreal-GAN, and present methodological advances and extensive experimental results elucidating brain aging heterogeneity in a cohort of 49,482 individuals from 11 studies. Five dominant patterns of brain atrophy were identified and quantified for each individual by respective measures, R-indices. Their associations with biomedical, lifestyle and genetic factors provide insights into the etiology of observed variances, suggesting their potential as brain endophenotypes for genetic and lifestyle risks. Furthermore, baseline R-indices predict disease progression and mortality, capturing early changes as supplementary prognostic markers. These R-indices establish a dimensional approach to measuring aging trajectories and related brain changes. They hold promise for precise diagnostics, especially at preclinical stages, facilitating personalized patient management and targeted clinical trial recruitment based on specific brain endophenotypic expression and prognosis.
    DOI:  https://doi.org/10.1038/s41591-024-03144-x
  21. J Clin Invest. 2024 Aug 15. pii: e174374. [Epub ahead of print]134(16):
    Posttranslationally modified self-peptides promote hypertension in mouse models.
    Nathaniel Bloodworth, Wei Chen, Kuniko Hunter, David Patrick, Amy Palubinsky, Elizabeth Phillips, Daniel Roeth, Markus Kalkum, Simon Mallal, Sean Davies, Mingfang Ao, Rocco Moretti, Jens Meiler, David G Harrison.
      Posttranslational modifications can enhance immunogenicity of self-proteins. In several conditions, including hypertension, systemic lupus erythematosus, and heart failure, isolevuglandins (IsoLGs) are formed by lipid peroxidation and covalently bond with protein lysine residues. Here, we show that the murine class I major histocompatibility complex (MHC-I) variant H-2Db uniquely presents isoLG-modified peptides and developed a computational pipeline that identifies structural features for MHC-I accommodation of such peptides. We identified isoLG-adducted peptides from renal proteins, including sodium glucose transporter 2, cadherin 16, Kelch domain-containing protein 7A, and solute carrier family 23, that are recognized by CD8+ T cells in tissues of hypertensive mice, induce T cell proliferation in vitro, and prime hypertension after adoptive transfer. Finally, we find patterns of isoLG-adducted antigen restriction in class I human leukocyte antigens that are similar to those in murine analogs. Thus, we have used a combined computational and experimental approach to define likely antigenic peptides in hypertension.
    Keywords:  Antigen; Cardiology; Hypertension; Immunology; MHC class 1
    DOI:  https://doi.org/10.1172/JCI174374
  22. Nat Genet. 2024 Aug;56(8): 1541
    RNU4-2 variants cause neurodevelopmental disorders.
    Safia Danovi.
      
    DOI:  https://doi.org/10.1038/s41588-024-01882-9
  23. J Clin Invest. 2024 Aug 15. pii: e183527. [Epub ahead of print]134(16):
    SLC44A2-mediated phenotypic switch of vascular smooth muscle cells contributes to aortic aneurysm.
    Mengen Xing, Wanqi Chen, Yachen Ji, Weihong Song.
      The phenotypic switch of vascular smooth cells (VSMCs) from a contractile to a synthetic state is associated with the development and progression of aortic aneurysm (AA). However, the mechanism underlying this process remains unclear. In this issue of the JCI, Song et al. identified SLC44A2 as a regulator of the phenotypic switch in VSMCs. Inhibition of SLC44A2 facilitated the switch to the synthetic state, contributing to the development of AA. Mechanistically, SLC44A2 interacted with NRP1 and ITGB3 to activate the TGF-β/SMAD signaling pathway, resulting in VSMCs with a contractile phenotype. Furthermore, VSMC-specific SLC44A2 overexpression by genetic or pharmacological manipulation reduced AA in mouse models. These findings suggest the potential of targeting the SLC44A2 signaling pathway for AA prevention and treatment.
    Keywords:  Molecular biology; Vascular biology
    DOI:  https://doi.org/10.1172/JCI183527
  24. Nature. 2024 Aug 15.
    How to win funding to talk about your science.
    Hannah Docter-Loeb.
      
    Keywords:  Careers; Communication; Funding
    DOI:  https://doi.org/10.1038/d41586-024-02656-3
  25. Nat Commun. 2024 Aug 15. 15(1): 7048
    Transporter-mediated depletion of extracellular proline directly contributes to plant pattern-triggered immunity against a bacterial pathogen.
    Conner J Rogan, Yin-Yuin Pang, Sophie D Mathews, Sydney E Turner, Alexandra J Weisberg, Silke Lehmann, Doris Rentsch, Jeffrey C Anderson.
      Plants possess cell surface-localized immune receptors that detect microbe-associated molecular patterns (MAMPs) and initiate defenses that provide effective resistance against microbial pathogens. Many MAMP-induced signaling pathways and cellular responses are known, yet how pattern-triggered immunity (PTI) limits pathogen growth in plants is poorly understood. Through a combined metabolomics and genetics approach, we discovered that plant-exuded proline is a virulence-inducing signal and nutrient for the bacterial pathogen Pseudomonas syringae, and that MAMP-induced depletion of proline from the extracellular spaces of Arabidopsis leaves directly contributes to PTI against P. syringae. We further show that MAMP-induced depletion of extracellular proline requires the amino acid transporter Lysine Histidine Transporter 1 (LHT1). This study demonstrates that depletion of a single extracellular metabolite is an effective component of plant induced immunity. Given the important role for amino acids as nutrients for microbial growth, their depletion at sites of infection may be a broadly effective means for defense against many pathogens.
    DOI:  https://doi.org/10.1038/s41467-024-51244-6
  26. Immunity. 2024 Aug 13. pii: S1074-7613(24)00361-3. [Epub ahead of print]57(8): 1716-1718
    Challenging the role of a NOX4-Piezo1 axis in neutrophil bactericidal function.
    Ulla G Knaus, Robert A Clark, William M Nauseef, Mary C Dinauer, Thomas L Leto, Vincent Jaquet.
      
    DOI:  https://doi.org/10.1016/j.immuni.2024.07.012
  27. Nature. 2024 Aug 14.
    Mitochondrial complex I promotes kidney cancer metastasis.
    Divya Bezwada, Luigi Perelli, Nicholas P Lesner, Ling Cai, Bailey Brooks, Zheng Wu, Hieu S Vu, Varun Sondhi, Daniel L Cassidy, Stacy Kasitinon, Sherwin Kelekar, Feng Cai, Arin B Aurora, McKenzie Patrick, Ashley Leach, Rashed Ghandour, Yuanyuan Zhang, Duyen Do, Phyllis McDaniel, Jessica Sudderth, Dennis Dumesnil, Sara House, Tracy Rosales, Alan M Poole, Yair Lotan, Solomon Woldu, Aditya Bagrodia, Xiaosong Meng, Jeffrey A Cadeddu, Prashant Mishra, Javier Garcia-Bermudez, Ivan Pedrosa, Payal Kapur, Kevin D Courtney, Craig R Malloy, Giannicola Genovese, Vitaly Margulis, Ralph J DeBerardinis.
      Most kidney cancers are metabolically dysfunctional1-4, but how this dysfunction affects cancer progression in humans is unknown. We infused 13C-labelled nutrients in over 80 patients with kidney cancer during surgical tumour resection. Labelling from [U-13C]glucose varies across subtypes, indicating that the kidney environment alone cannot account for all tumour metabolic reprogramming. Compared with the adjacent kidney, clear cell renal cell carcinomas (ccRCCs) display suppressed labelling of tricarboxylic acid (TCA) cycle intermediates in vivo and in ex vivo organotypic cultures, indicating that suppressed labelling is tissue intrinsic. [1,2-13C]acetate and [U-13C]glutamine infusions in patients, coupled with measurements of respiration in isolated human kidney and tumour mitochondria, reveal lower electron transport chain activity in ccRCCs that contributes to decreased oxidative and enhanced reductive TCA cycle labelling. However, ccRCC metastases unexpectedly have enhanced TCA cycle labelling compared with that of primary ccRCCs, indicating a divergent metabolic program during metastasis in patients. In mice, stimulating respiration or NADH recycling in kidney cancer cells is sufficient to promote metastasis, whereas inhibiting electron transport chain complex I decreases metastasis. These findings in humans and mice indicate that metabolic properties and liabilities evolve during kidney cancer progression, and that mitochondrial function is limiting for metastasis but not growth at the original site.
    DOI:  https://doi.org/10.1038/s41586-024-07812-3
  28. Cell. 2024 Aug 05. pii: S0092-8674(24)00780-3. [Epub ahead of print]
    The molecular architecture of the nuclear basket.
    Digvijay Singh, Neelesh Soni, Joshua Hutchings, Ignacia Echeverria, Farhaz Shaikh, Madeleine Duquette, Sergey Suslov, Zhixun Li, Trevor van Eeuwen, Kelly Molloy, Yi Shi, Junjie Wang, Qiang Guo, Brian T Chait, Javier Fernandez-Martinez, Michael P Rout, Andrej Sali, Elizabeth Villa.
      The nuclear pore complex (NPC) is the sole mediator of nucleocytoplasmic transport. Despite great advances in understanding its conserved core architecture, the peripheral regions can exhibit considerable variation within and between species. One such structure is the cage-like nuclear basket. Despite its crucial roles in mRNA surveillance and chromatin organization, an architectural understanding has remained elusive. Using in-cell cryo-electron tomography and subtomogram analysis, we explored the NPC's structural variations and the nuclear basket across fungi (yeast; S. cerevisiae), mammals (mouse; M. musculus), and protozoa (T. gondii). Using integrative structural modeling, we computed a model of the basket in yeast and mammals that revealed how a hub of nucleoporins (Nups) in the nuclear ring binds to basket-forming Mlp/Tpr proteins: the coiled-coil domains of Mlp/Tpr form the struts of the basket, while their unstructured termini constitute the basket distal densities, which potentially serve as a docking site for mRNA preprocessing before nucleocytoplasmic transport.
    Keywords:  NPC; chromatin organization; cross-linking mass spectrometry; cryo-electron tomography; cryo-focused-ion-beam milling; in-cell structural biology; integrative modeling; mRNA transport; nuclear basket; nuclear pore complex; subtomogram analysis
    DOI:  https://doi.org/10.1016/j.cell.2024.07.020
  29. Nat Commun. 2024 Aug 14. 15(1): 6970
    Inhibition of glycosphingolipid synthesis with eliglustat in combination with immune checkpoint inhibitors in advanced cancers: preclinical evidence and phase I clinical trial.
    Liang Dong, Zhi Cao, Meixia Chen, Yang Liu, Xinran Ma, Yuting Lu, Yan Zhang, Kaichao Feng, Yang Zhang, Zhenzhen Meng, Qingming Yang, Yao Wang, Zhiqiang Wu, Weidong Han.
      Glycosphingolipids (GSLs) are abundantly expressed in cancer cells. The effects of GSL-targeted immunotherapies are not fully understood. Here, we show that the inhibition of GSL synthesis with the UDP-glucose ceramide glucosyltransferase inhibitor eliglustat can increase the exposure of the major histocompatibility complex (MHC) and tumour antigen peptides, enhancing the antitumour response of CD8+ T cells in a range of tumour models. We therefore conducted a proof-of-concept phase I trial on the combination of eliglustat and an anti-PD-1 antibody for the treatment of advanced cancers (NCT04944888). The primary endpoints were safety and feasibility, and the secondary endpoint was antitumor activity. All prespecified endpoints were met. Among the 31 enrolled patients, only 1 patient experienced a grade 3 adverse event (AE), and no grade 4 AEs were observed. The objective response rate was 22.6% and the disease control rate reached 71%. Of the 8 patients with proficient mismatch repair/microsatellite stable (pMMR/MSS) colorectal cancer, one achieved complete response and two each had partial response and stable disease. In summary, inhibiting the synthesis of GSLs might represent an effective immunotherapy approach.
    DOI:  https://doi.org/10.1038/s41467-024-51495-3
  30. Commun Biol. 2024 Aug 14. 7(1): 996
    ScreenDMT reveals DiHOMEs are replicably inversely associated with BMI and stimulate adipocyte calcium influx.
    Jonathan M Dreyfuss, Vera Djordjilović, Hui Pan, Valerie Bussberg, Allison M MacDonald, Niven R Narain, Michael A Kiebish, Matthias Blüher, Yu-Hua Tseng, Matthew D Lynes.
      Activating brown adipose tissue (BAT) improves systemic metabolism, making it a promising target for metabolic syndrome. BAT is activated by 12,13-dihydroxy-9Z-octadecenoic acid (12,13-diHOME), which we previously identified to be inversely associated with BMI and which directly improves metabolism in multiple tissues. Here we profile plasma lipidomics from 83 people and test which lipids' association with BMI replicates in a concordant direction using our novel tool ScreenDMT, whose power and validity we demonstrate via mathematical proofs and simulations. We find that the linoleic acid diols 12,13-diHOME and 9,10-diHOME are both replicably inversely associated with BMI and mechanistically activate calcium influx in mouse brown and white adipocytes in vitro, which implicates this signaling pathway and 9,10-diHOME as candidate therapeutic targets. ScreenDMT can be applied to test directional mediation, directional replication, and qualitative interactions, such as identifying biomarkers whose association is shared (replication) or opposite (qualitative interaction) across diverse populations.
    DOI:  https://doi.org/10.1038/s42003-024-06646-z
  31. Cell Genom. 2024 Aug 09. pii: S2666-979X(24)00234-9. [Epub ahead of print] 100630
    Genetic and functional analysis of Raynaud's syndrome implicates loci in vasculature and immunity.
    FinnGen, Estonian Biobank research team
      Raynaud's syndrome is a dysautonomia where exposure to cold causes vasoconstriction and hypoxia, particularly in the extremities. We performed meta-analysis in four cohorts and discovered eight loci (ADRA2A, IRX1, NOS3, ACVR2A, TMEM51, PCDH10-DT, HLA, and RAB6C) where ADRA2A, ACVR2A, NOS3, TMEM51, and IRX1 co-localized with expression quantitative trait loci (eQTLs), particularly in distal arteries. CRISPR gene editing further showed that ADRA2A and NOS3 loci modified gene expression and in situ RNAscope clarified the specificity of ADRA2A in small vessels and IRX1 around small capillaries in the skin. A functional contraction assay in the cold showed lower contraction in ADRA2A-deficient and higher contraction in ADRA2A-overexpressing smooth muscle cells. Overall, our study highlights the power of genome-wide association testing with functional follow-up as a method to understand complex diseases. The results indicate temperature-dependent adrenergic signaling through ADRA2A, effects at the microvasculature by IRX1, endothelial signaling by NOS3, and immune mechanisms by the HLA locus in Raynaud's syndrome.
    DOI:  https://doi.org/10.1016/j.xgen.2024.100630
  32. Nat Commun. 2024 Aug 12. 15(1): 6914
    Defective mitochondrial COX1 translation due to loss of COX14 function triggers ROS-induced inflammation in mouse liver.
    Abhishek Aich, Angela Boshnakovska, Steffen Witte, Tanja Gall, Kerstin Unthan-Fechner, Roya Yousefi, Arpita Chowdhury, Drishan Dahal, Aditi Methi, Svenja Kaufmann, Ivan Silbern, Jan Prochazka, Zuzana Nichtova, Marcela Palkova, Miles Raishbrook, Gizela Koubkova, Radislav Sedlacek, Simon E Tröder, Branko Zevnik, Dietmar Riedel, Susann Michanski, Wiebke Möbius, Philipp Ströbel, Christian Lüchtenborg, Patrick Giavalisco, Henning Urlaub, Andre Fischer, Britta Brügger, Stefan Jakobs, Peter Rehling.
      Mitochondrial oxidative phosphorylation (OXPHOS) fuels cellular ATP demands. OXPHOS defects lead to severe human disorders with unexplained tissue specific pathologies. Mitochondrial gene expression is essential for OXPHOS biogenesis since core subunits of the complexes are mitochondrial-encoded. COX14 is required for translation of COX1, the central mitochondrial-encoded subunit of complex IV. Here we describe a COX14 mutant mouse corresponding to a patient with complex IV deficiency. COX14M19I mice display broad tissue-specific pathologies. A hallmark phenotype is severe liver inflammation linked to release of mitochondrial RNA into the cytosol sensed by RIG-1 pathway. We find that mitochondrial RNA release is triggered by increased reactive oxygen species production in the deficiency of complex IV. Additionally, we describe a COA3Y72C mouse, affected in an assembly factor that cooperates with COX14 in early COX1 biogenesis, which displays a similar yet milder inflammatory phenotype. Our study provides insight into a link between defective mitochondrial gene expression and tissue-specific inflammation.
    DOI:  https://doi.org/10.1038/s41467-024-51109-y
  33. Nat Biotechnol. 2024 Aug 09.
    Protein language model enables fast and sensitive remote homolog detection.
      
    DOI:  https://doi.org/10.1038/s41587-024-02359-0
  34. Nat Immunol. 2024 Aug 12.
    Tracing the origins of lung fibrosis.
    Christopher D Buckley, Kim S Midwood.
      
    DOI:  https://doi.org/10.1038/s41590-024-01934-6
  35. Proc Natl Acad Sci U S A. 2024 Aug 20. 121(34): e2403392121
    MAVS Cys508 palmitoylation promotes its aggregation on the mitochondrial outer membrane and antiviral innate immunity.
    Yinong Liu, Dan Hou, Wenzhe Chen, Xuan Lu, Garrison P Komaniecki, Yilai Xu, Tao Yu, Sophia M Zhang, Maurine E Linder, Hening Lin.
      Cysteine palmitoylation or S-palmitoylation catalyzed by the ZDHHC family of acyltransferases regulates the biological function of numerous mammalian proteins as well as viral proteins. However, understanding of the role of S-palmitoylation in antiviral immunity against RNA viruses remains very limited. The adaptor protein MAVS forms functionally essential prion-like aggregates upon activation by viral RNA-sensing RIG-I-like receptors. Here, we identify that MAVS, a C-terminal tail-anchored mitochondrial outer membrane protein, is S-palmitoylated by ZDHHC7 at Cys508, a residue adjacent to the tail-anchor transmembrane helix. Using superresolution microscopy and other biochemical techniques, we found that the mitochondrial localization of MAVS at resting state mainly depends on its transmembrane tail-anchor, without regulation by Cys508 S-palmitoylation. However, upon viral infection, MAVS S-palmitoylation stabilizes its aggregation on the mitochondrial outer membrane and thus promotes subsequent propagation of antiviral signaling. We further show that inhibition of MAVS S-palmitoylation increases the host susceptibility to RNA virus infection, highlighting the importance of S-palmitoylation in the antiviral innate immunity. Also, our results indicate ZDHHC7 as a potential therapeutic target for MAVS-related autoimmune diseases.
    Keywords:  MAVS; ZDHHC7; antiviral innate immunity; palmitoylation; tail-anchored proteins
    DOI:  https://doi.org/10.1073/pnas.2403392121
  36. J Exp Med. 2024 Sep 02. pii: e20231820. [Epub ahead of print]221(9):
    ACLY and ACSS2 link nutrient-dependent chromatin accessibility to CD8 T cell effector responses.
    Irem Kaymak, McLane J Watson, Brandon M Oswald, Shixin Ma, Benjamin K Johnson, Lisa M DeCamp, Batsirai M Mabvakure, Katarzyna M Luda, Eric H Ma, Kin Lau, Zhen Fu, Brejnev Muhire, Susan M Kitchen-Goosen, Alexandra Vander Ark, Michael S Dahabieh, Bozena Samborska, Matthew Vos, Hui Shen, Zi Peng Fan, Thomas P Roddy, Gillian A Kingsbury, Cristovão M Sousa, Connie M Krawczyk, Kelsey S Williams, Ryan D Sheldon, Susan M Kaech, Dominic G Roy, Russell G Jones.
      Coordination of cellular metabolism is essential for optimal T cell responses. Here, we identify cytosolic acetyl-CoA production as an essential metabolic node for CD8 T cell function in vivo. We show that CD8 T cell responses to infection depend on acetyl-CoA derived from citrate via the enzyme ATP citrate lyase (ACLY). However, ablation of ACLY triggers an alternative, acetate-dependent pathway for acetyl-CoA production mediated by acyl-CoA synthetase short-chain family member 2 (ACSS2). Mechanistically, acetate fuels both the TCA cycle and cytosolic acetyl-CoA production, impacting T cell effector responses, acetate-dependent histone acetylation, and chromatin accessibility at effector gene loci. When ACLY is functional, ACSS2 is not required, suggesting acetate is not an obligate metabolic substrate for CD8 T cell function. However, loss of ACLY renders CD8 T cells dependent on acetate (via ACSS2) to maintain acetyl-CoA production and effector function. Together, ACLY and ACSS2 coordinate cytosolic acetyl-CoA production in CD8 T cells to maintain chromatin accessibility and T cell effector function.
    DOI:  https://doi.org/10.1084/jem.20231820
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