bims-nimamd Biomed News
on Neuroimmunity and neuroinflammation in ageing and metabolic disease
Issue of 2023‒10‒22
38 papers selected by
Fawaz Alzaïd, Sorbonne Université
  1. PD-1 takes control.
  2. Just be kind.
  3. Unraveling age-specific complexity in the human T cell compartment.
  4. Saving ribosomal proteins for later.
  5. A guide to studying mitochondria transfer.
  6. FSH and ApoE4 contribute to Alzheimer's disease-like pathogenesis via C/EBPβ/δ-secretase in female mice.
  7. Immunological signature.
  8. Genome-wide association meta-analysis identifies risk loci for abdominal aortic aneurysm and highlights PCSK9 as a therapeutic target.
  9. Obesity dysregulates the pulmonary antiviral immune response.
  10. Milkshake neuroscience: how the brain nudges us toward fatty foods.
  11. Hijacking host ribosomes via tRNA mimicry.
  12. Anti-ageing molecule boosts fertility in ageing mice.
  13. Fibrocystin/Polyductin releases a C-terminal fragment that translocates into mitochondria and suppresses cystogenesis.
  14. Structural basis for recruitment of TASL by SLC15A4 in human endolysosomal TLR signaling.
  15. Phage therapy in noncommunicable diseases.
  16. Systematic differences in discovery of genetic effects on gene expression and complex traits.
  17. The SMN complex drives structural changes in human snRNAs to enable snRNP assembly.
  18. Reprogramming of cis-regulatory networks during skeletal muscle atrophy in male mice.
  19. Zfp335 establishes eTreg lineage and neonatal immune tolerance by targeting Hadha-mediated fatty acid oxidation.
  20. How to rebuild trust in science: NIH director nominee fields questions.
  21. Adaptive preservation of orphan ribosomal proteins in chaperone-dispersed condensates.
  22. A mouse model with high clonal barcode diversity for joint lineage, transcriptomic, and epigenomic profiling in single cells.
  23. Gut insulin action protects from hepatocarcinogenesis in diabetic mice comorbid with nonalcoholic steatohepatitis.
  24. A conformation-locking inhibitor of SLC15A4 with TASL proteostatic anti-inflammatory activity.
  25. The transcription factor Zeb1 controls homeostasis and function of type 1 conventional dendritic cells.
  26. Polyamine metabolism controls B-to-Z DNA transition to orchestrate DNA sensor cGAS activity.
  27. RING finger protein 13 protects against nonalcoholic steatohepatitis by targeting STING-relayed signaling pathways.
  28. Long-term super-resolution inner mitochondrial membrane imaging with a lipid probe.
  29. Molecular mechanisms controlling the biogenesis of the TGF-β signal Vg1.
  30. Conserved enhancers control notochord expression of vertebrate Brachyury.
  31. Clinical utility of polygenic scores for cardiometabolic disease in Arabs.
  32. Characterization of the responses of brain macrophages to focused ultrasound-mediated blood-brain barrier opening.
  33. Fluorescence lifetime of injected indocyanine green as a universal marker of solid tumours in patients.
  34. Bacterial histones unveiled.
  35. A spatial sequencing atlas of age-induced changes in the lung during influenza infection.
  36. A20 regulates lymphocyte adhesion in murine neuroinflammation by restricting endothelial ICOSL expression in the CNS.
  37. A Legionella toxin exhibits tRNA mimicry and glycosyl transferase activity to target the translation machinery and trigger a ribotoxic stress response.
  38. SRCAP mutations drive clonal hematopoiesis through epigenetic and DNA repair dysregulation.
  1. Nat Immunol. 2023 Oct 16.
    PD-1 takes control.
    Stephanie Houston.
      
    DOI:  https://doi.org/10.1038/s41590-023-01677-w
  2. Science. 2023 Oct 20. 382(6668): 338
    Just be kind.
    Roel Snieder.
      
    DOI:  https://doi.org/10.1126/science.adl3599
  3. Nat Immunol. 2023 Oct 16.
    Unraveling age-specific complexity in the human T cell compartment.
      
    DOI:  https://doi.org/10.1038/s41590-023-01653-4
  4. Nat Cell Biol. 2023 Oct 16.
    Saving ribosomal proteins for later.
    Joshua J Black, Rachel Green.
      
    DOI:  https://doi.org/10.1038/s41556-023-01251-4
  5. Nat Cell Biol. 2023 Oct 18.
    A guide to studying mitochondria transfer.
    Snigdha Tiash, Jonathan Robert Brestoff, Clair Crewe.
      
    DOI:  https://doi.org/10.1038/s41556-023-01246-1
  6. Nat Commun. 2023 Oct 18. 14(1): 6577
    FSH and ApoE4 contribute to Alzheimer's disease-like pathogenesis via C/EBPβ/δ-secretase in female mice.
    Jing Xiong, Seong Su Kang, Mengmeng Wang, Zhihao Wang, Yiyuan Xia, Jianming Liao, Xia Liu, Shan-Ping Yu, Zhaohui Zhang, Vitaly Ryu, Tony Yuen, Mone Zaidi, Keqiang Ye.
      Alzheimer's disease (AD) is the most common dementia. It is known that women with one ApoE4 allele display greater risk and earlier onset of AD compared with men. In mice, we previously showed that follicle-stimulating hormone (FSH), a gonadotropin that rises in post-menopausal females, activates its receptor FSHR in the hippocampus, to drive AD-like pathology and cognitive impairment. Here we show in mice that ApoE4 and FSH jointly trigger AD-like pathogenesis by activating C/EBPβ/δ-secretase signaling. ApoE4 and FSH additively activate C/EBPβ/δ-secretase pathway that mediates APP and Tau proteolytic fragmentation, stimulating Aβ and neurofibrillary tangles. Ovariectomy-provoked AD-like pathologies and cognitive defects in female ApoE4-TR mice are ameliorated by anti-FSH antibody treatment. FSH administration facilitates AD-like pathologies in both young male and female ApoE4-TR mice. Furthermore, FSH stimulates AD-like pathologies and cognitive defects in ApoE4-TR mice, but not ApoE3-TR mice. Our findings suggest that in mice, augmented FSH in females with ApoE4 but not ApoE3 genotype increases vulnerability to AD-like process by activating C/EBPβ/δ-secretase signalling.
    DOI:  https://doi.org/10.1038/s41467-023-42282-7
  7. Nat Immunol. 2023 Oct 16.
    Immunological signature.
    Ioana Visan.
      
    DOI:  https://doi.org/10.1038/s41590-023-01676-x
  8. Nat Genet. 2023 Oct 16.
    Genome-wide association meta-analysis identifies risk loci for abdominal aortic aneurysm and highlights PCSK9 as a therapeutic target.
    DiscovEHR
      Abdominal aortic aneurysm (AAA) is a common disease with substantial heritability. In this study, we performed a genome-wide association meta-analysis from 14 discovery cohorts and uncovered 141 independent associations, including 97 previously unreported loci. A polygenic risk score derived from meta-analysis explained AAA risk beyond clinical risk factors. Genes at AAA risk loci indicate involvement of lipid metabolism, vascular development and remodeling, extracellular matrix dysregulation and inflammation as key mechanisms in AAA pathogenesis. These genes also indicate overlap between the development of AAA and other monogenic aortopathies, particularly via transforming growth factor β signaling. Motivated by the strong evidence for the role of lipid metabolism in AAA, we used Mendelian randomization to establish the central role of nonhigh-density lipoprotein cholesterol in AAA and identified the opportunity for repurposing of proprotein convertase, subtilisin/kexin-type 9 (PCSK9) inhibitors. This was supported by a study demonstrating that PCSK9 loss of function prevented the development of AAA in a preclinical mouse model.
    DOI:  https://doi.org/10.1038/s41588-023-01510-y
  9. Nat Commun. 2023 Oct 19. 14(1): 6607
    Obesity dysregulates the pulmonary antiviral immune response.
    Mark Almond, Hugo A Farne, Millie M Jackson, Akhilesh Jha, Orestis Katsoulis, Oliver Pitts, Tanushree Tunstall, Eteri Regis, Jake Dunning, Adam J Byrne, Patrick Mallia, Onn Min Kon, Ken A Saunders, Karen D Simpson, Robert J Snelgrove, Peter J M Openshaw, Michael R Edwards, Wendy S Barclay, Liam M Heaney, Sebastian L Johnston, Aran Singanayagam.
      Obesity is a well-recognized risk factor for severe influenza infections but the mechanisms underlying susceptibility are poorly understood. Here, we identify that obese individuals have deficient pulmonary antiviral immune responses in bronchoalveolar lavage cells but not in bronchial epithelial cells or peripheral blood dendritic cells. We show that the obese human airway metabolome is perturbed with associated increases in the airway concentrations of the adipokine leptin which correlated negatively with the magnitude of ex vivo antiviral responses. Exogenous pulmonary leptin administration in mice directly impaired antiviral type I interferon responses in vivo and ex vivo in cultured airway macrophages. Obese individuals hospitalised with influenza showed dysregulated upper airway immune responses. These studies provide insight into mechanisms driving propensity to severe influenza infections in obesity and raise the potential for development of leptin manipulation or interferon administration as novel strategies for conferring protection from severe infections in obese higher risk individuals.
    DOI:  https://doi.org/10.1038/s41467-023-42432-x
  10. Nature. 2023 Oct 16.
    Milkshake neuroscience: how the brain nudges us toward fatty foods.
    Max Kozlov.
      
    Keywords:  Human behaviour; Neuroscience; Sensory systems
    DOI:  https://doi.org/10.1038/d41586-023-03243-8
  11. Nat Cell Biol. 2023 Oct 19.
    Hijacking host ribosomes via tRNA mimicry.
    Saori Uematsu, Shu-Bing Qian.
      
    DOI:  https://doi.org/10.1038/s41556-023-01249-y
  12. Nature. 2023 Oct 16.
    Anti-ageing molecule boosts fertility in ageing mice.
    Gemma Conroy.
      
    Keywords:  Ageing; Cell biology; Molecular biology
    DOI:  https://doi.org/10.1038/d41586-023-03224-x
  13. Nat Commun. 2023 Oct 16. 14(1): 6513
    Fibrocystin/Polyductin releases a C-terminal fragment that translocates into mitochondria and suppresses cystogenesis.
    Rebecca V Walker, Qin Yao, Hangxue Xu, Anthony Maranto, Kristen F Swaney, Sreekumar Ramachandran, Rong Li, Laura Cassina, Brian M Polster, Patricia Outeda, Alessandra Boletta, Terry Watnick, Feng Qian.
      Fibrocystin/Polyductin (FPC), encoded by PKHD1, is associated with autosomal recessive polycystic kidney disease (ARPKD), yet its precise role in cystogenesis remains unclear. Here we show that FPC undergoes complex proteolytic processing in developing kidneys, generating three soluble C-terminal fragments (ICDs). Notably, ICD15, contains a novel mitochondrial targeting sequence at its N-terminus, facilitating its translocation into mitochondria. This enhances mitochondrial respiration in renal epithelial cells, partially restoring impaired mitochondrial function caused by FPC loss. FPC inactivation leads to abnormal ultrastructural morphology of mitochondria in kidney tubules without cyst formation. Moreover, FPC inactivation significantly exacerbates renal cystogenesis and triggers severe pancreatic cystogenesis in a Pkd1 mouse mutant Pkd1V/V in which cleavage of Pkd1-encoded Polycystin-1 at the GPCR Proteolysis Site is blocked. Deleting ICD15 enhances renal cystogenesis without inducing pancreatic cysts in Pkd1V/V mice. These findings reveal a direct link between FPC and a mitochondrial pathway through ICD15 cleavage, crucial for cystogenesis mechanisms.
    DOI:  https://doi.org/10.1038/s41467-023-42196-4
  14. Nat Commun. 2023 Oct 20. 14(1): 6627
    Structural basis for recruitment of TASL by SLC15A4 in human endolysosomal TLR signaling.
    Xudong Chen, Min Xie, Sensen Zhang, Marta Monguió-Tortajada, Jian Yin, Chang Liu, Youqi Zhang, Maeva Delacrétaz, Mingyue Song, Yixue Wang, Lin Dong, Qiang Ding, Boda Zhou, Xiaolin Tian, Haiteng Deng, Lina Xu, Xiaohui Liu, Zi Yang, Qing Chang, Jie Na, Wenwen Zeng, Giulio Superti-Furga, Manuele Rebsamen, Maojun Yang.
      Toll-like receptors (TLRs) are a class of proteins that play critical roles in recognizing pathogens and initiating innate immune responses. TASL, a recently identified innate immune adaptor protein for endolysosomal TLR7/8/9 signaling, is recruited by the lysosomal proton-coupled amino-acid transporter SLC15A4, and then activates IRF5, which in turn triggers the transcription of type I interferons and cytokines. Here, we report three cryo-electron microscopy (cryo-EM) structures of human SLC15A4 in the apo monomeric and dimeric state and as a TASL-bound complex. The apo forms are in an outward-facing conformation, with the dimeric form showing an extensive interface involving four cholesterol molecules. The structure of the TASL-bound complex reveals an unprecedented interaction mode with solute carriers. During the recruitment of TASL, SLC15A4 undergoes a conformational change from an outward-facing, lysosomal lumen-exposed state to an inward-facing state to form a binding pocket, allowing the N-terminal helix of TASL to be inserted into. Our findings provide insights into the molecular basis of regulatory switch involving a human solute carrier and offers an important framework for structure-guided drug discovery targeting SLC15A4-TASL-related human autoimmune diseases.
    DOI:  https://doi.org/10.1038/s41467-023-42210-9
  15. Science. 2023 Oct 20. 382(6668): 266-267
    Phage therapy in noncommunicable diseases.
    Denise Kviatcovsky, Rafael Valdés-Mas, Sara Federici, Eran Elinav.
      Bacteriophages have potential as suppressors of disease-contributing commensal bacteria.
    DOI:  https://doi.org/10.1126/science.adh2718
  16. Nat Genet. 2023 Oct 19.
    Systematic differences in discovery of genetic effects on gene expression and complex traits.
    Hakhamanesh Mostafavi, Jeffrey P Spence, Sahin Naqvi, Jonathan K Pritchard.
      Most signals in genome-wide association studies (GWAS) of complex traits implicate noncoding genetic variants with putative gene regulatory effects. However, currently identified regulatory variants, notably expression quantitative trait loci (eQTLs), explain only a small fraction of GWAS signals. Here, we show that GWAS and cis-eQTL hits are systematically different: eQTLs cluster strongly near transcription start sites, whereas GWAS hits do not. Genes near GWAS hits are enriched in key functional annotations, are under strong selective constraint and have complex regulatory landscapes across different tissue/cell types, whereas genes near eQTLs are depleted of most functional annotations, show relaxed constraint, and have simpler regulatory landscapes. We describe a model to understand these observations, including how natural selection on complex traits hinders discovery of functionally relevant eQTLs. Our results imply that GWAS and eQTL studies are systematically biased toward different types of variant, and support the use of complementary functional approaches alongside the next generation of eQTL studies.
    DOI:  https://doi.org/10.1038/s41588-023-01529-1
  17. Nat Commun. 2023 Oct 18. 14(1): 6580
    The SMN complex drives structural changes in human snRNAs to enable snRNP assembly.
    Josef Pánek, Adriana Roithová, Nenad Radivojević, Michal Sýkora, Archana Bairavasundaram Prusty, Nicholas Huston, Han Wan, Anna Marie Pyle, Utz Fischer, David Staněk.
      Spliceosomal snRNPs are multicomponent particles that undergo a complex maturation pathway. Human Sm-class snRNAs are generated as 3'-end extended precursors, which are exported to the cytoplasm and assembled together with Sm proteins into core RNPs by the SMN complex. Here, we provide evidence that these pre-snRNA substrates contain compact, evolutionarily conserved secondary structures that overlap with the Sm binding site. These structural motifs in pre-snRNAs are predicted to interfere with Sm core assembly. We model structural rearrangements that lead to an open pre-snRNA conformation compatible with Sm protein interaction. The predicted rearrangement pathway is conserved in Metazoa and requires an external factor that initiates snRNA remodeling. We show that the essential helicase Gemin3, which is a component of the SMN complex, is crucial for snRNA structural rearrangements during snRNP maturation. The SMN complex thus facilitates ATP-driven structural changes in snRNAs that expose the Sm site and enable Sm protein binding.
    DOI:  https://doi.org/10.1038/s41467-023-42324-0
  18. Nat Commun. 2023 Oct 18. 14(1): 6581
    Reprogramming of cis-regulatory networks during skeletal muscle atrophy in male mice.
    Hongchun Lin, Hui Peng, Yuxiang Sun, Meijun Si, Jiao Wu, Yanlin Wang, Sandhya S Thomas, Zheng Sun, Zhaoyong Hu.
      A comprehensive atlas of cis-regulatory elements and their dynamic activity is necessary to understand the transcriptional basis of cellular structure maintenance, metabolism, and responses to the environment. Here we show, using matched single-nucleus chromatin accessibility and RNA-sequencing from juvenile male C57BL6 mice, an atlas of accessible chromatin regions in both normal and denervated skeletal muscles. We identified cell-type-specific cis-regulatory networks, highlighting the dynamic regulatory circuits mediating transitions between myonuclear types. Through comparison of normal and perturbed muscle, we delineated the reprogramming of cis-regulatory networks in response to denervation, described the interplay of promoters/enhancers and target genes. We further unveil a hierarchical structure of transcription factors that delineate a regulatory network in atrophic muscle, identifying ELK4 as a key atrophy-related transcription factor that instigates muscle atrophy through TGF-β1 regulation. This study furnishes a rich genomic resource, essential for decoding the regulatory dynamics of skeletal muscle in both physiological and pathological states.
    DOI:  https://doi.org/10.1038/s41467-023-42313-3
  19. J Clin Invest. 2023 Oct 16. pii: e166628. [Epub ahead of print]133(20):
    Zfp335 establishes eTreg lineage and neonatal immune tolerance by targeting Hadha-mediated fatty acid oxidation.
    Xin Wang, Lina Sun, Biao Yang, Wenhua Li, Cangang Zhang, Xiaofeng Yang, Yae Sun, Xiaonan Shen, Yang Gao, Bomiao Ju, Yafeng Gao, Dan Liu, Jiapeng Song, Xiaoxuan Jia, Yanhong Su, Anjun Jiao, Haiyan Liu, Lianjun Zhang, Lan He, Lei Lei, WanJun Chen, Baojun Zhang.
      Regulatory T cells (Tregs) are instrumental in maintaining immune tolerance and preventing destructive autoimmunity, but how heterogeneous Treg populations are established remains largely unknown. Here, we show that Zfp335 deletion in Tregs failed to differentiate into effector Tregs (eTregs) and lose Treg-suppressive function and that KO mice exhibited early-onset lethal autoimmune inflammation with unrestricted activation of conventional T cells. Single-cell RNA-Seq analyses revealed that Zfp335-deficient Tregs lacked a eTreg population and showed dramatic accumulation of a dysfunctional Treg subset. Mechanistically, Zfp335-deficient Tregs displayed reduced oxidative phosphorylation and dysfunctional mitochondrial activity. Further studies revealed that Zfp335 controlled eTreg differentiation by regulating fatty acid oxidation (FAO) through direct targeting of the FAO enzyme Hadha. Importantly, we demonstrate a positive correlation between ZNF335 and HADHA expression in human eTregs. Our findings reveal that Zfp335 controls FAO-driven eTreg differentiation to establish immune tolerance.
    Keywords:  Adaptive immunity; Autoimmune diseases; Autoimmunity; Immunology; T cells
    DOI:  https://doi.org/10.1172/JCI166628
  20. Nature. 2023 Oct 19.
    How to rebuild trust in science: NIH director nominee fields questions.
    Max Kozlov.
      
    Keywords:  Policy; Politics; Public health
    DOI:  https://doi.org/10.1038/d41586-023-03263-4
  21. Nat Cell Biol. 2023 Oct 16.
    Adaptive preservation of orphan ribosomal proteins in chaperone-dispersed condensates.
    Asif Ali, Rania Garde, Olivia C Schaffer, Jared A M Bard, Kabir Husain, Samantha Keyport Kik, Kathleen A Davis, Sofia Luengo-Woods, Maya G Igarashi, D Allan Drummond, Allison H Squires, David Pincus.
      Ribosome biogenesis is among the most resource-intensive cellular processes, with ribosomal proteins accounting for up to half of all newly synthesized proteins in eukaryotic cells. During stress, cells shut down ribosome biogenesis in part by halting rRNA synthesis, potentially leading to massive accumulation of aggregation-prone 'orphan' ribosomal proteins (oRPs). Here we show that, during heat shock in yeast and human cells, oRPs accumulate as reversible peri-nucleolar condensates recognized by the Hsp70 co-chaperone Sis1/DnaJB6. oRP condensates are liquid-like in cell-free lysate but solidify upon depletion of Sis1 or inhibition of Hsp70. When cells recover from heat shock, oRP condensates disperse in a Sis1- and Hsp70-dependent manner, and the oRP constituents are incorporated into functional ribosomes in the cytosol, enabling cells to efficiently resume growth. Preserving biomolecules in reversible condensates-like mRNAs in cytosolic stress granules and oRPs at the nucleolar periphery-may be a primary function of the Hsp70 chaperone system.
    DOI:  https://doi.org/10.1038/s41556-023-01253-2
  22. Cell. 2023 Oct 12. pii: S0092-8674(23)01040-1. [Epub ahead of print]
    A mouse model with high clonal barcode diversity for joint lineage, transcriptomic, and epigenomic profiling in single cells.
    Li Li, Sarah Bowling, Sean E McGeary, Qi Yu, Bianca Lemke, Karel Alcedo, Yuemeng Jia, Xugeng Liu, Mark Ferreira, Allon M Klein, Shou-Wen Wang, Fernando D Camargo.
      Cellular lineage histories and their molecular states encode fundamental principles of tissue development and homeostasis. Current lineage-recording mouse models have insufficient barcode diversity and single-cell lineage coverage for profiling tissues composed of millions of cells. Here, we developed DARLIN, an inducible Cas9 barcoding mouse line that utilizes terminal deoxynucleotidyl transferase (TdT) and 30 CRISPR target sites. DARLIN is inducible, generates massive lineage barcodes across tissues, and enables the detection of edited barcodes in ∼70% of profiled single cells. Using DARLIN, we examined fate bias within developing hematopoietic stem cells (HSCs) and revealed unique features of HSC migration. Additionally, we established a protocol for joint transcriptomic and epigenomic single-cell measurements with DARLIN and found that cellular clonal memory is associated with genome-wide DNA methylation rather than gene expression or chromatin accessibility. DARLIN will enable the high-resolution study of lineage relationships and their molecular signatures in diverse tissues and physiological contexts.
    Keywords:  DNA methylation; hematopoiesis; lineage tracing; multiomics; single cell
    DOI:  https://doi.org/10.1016/j.cell.2023.09.019
  23. Nat Commun. 2023 Oct 18. 14(1): 6584
    Gut insulin action protects from hepatocarcinogenesis in diabetic mice comorbid with nonalcoholic steatohepatitis.
    Kotaro Soeda, Takayoshi Sasako, Kenichiro Enooku, Naoto Kubota, Naoki Kobayashi, Yoshiko Matsumoto Ikushima, Motoharu Awazawa, Ryotaro Bouchi, Gotaro Toda, Tomoharu Yamada, Takuma Nakatsuka, Ryosuke Tateishi, Miwako Kakiuchi, Shogo Yamamoto, Kenji Tatsuno, Koji Atarashi, Wataru Suda, Kenya Honda, Hiroyuki Aburatani, Toshimasa Yamauchi, Mitsuhiro Fujishiro, Tetsuo Noda, Kazuhiko Koike, Takashi Kadowaki, Kohjiro Ueki.
      Diabetes is known to increase the risk of nonalcoholic steatohepatitis (NASH) and hepatocellular carcinoma (HCC). Here we treat male STAM (STelic Animal Model) mice, which develop diabetes, NASH and HCC associated with dysbiosis upon low-dose streptozotocin and high-fat diet (HFD), with insulin or phlorizin. Although both treatments ameliorate hyperglycemia and NASH, insulin treatment alone lead to suppression of HCC accompanied by improvement of dysbiosis and restoration of antimicrobial peptide production. There are some similarities in changes of microflora from insulin-treated patients comorbid with diabetes and NASH. Insulin treatment, however, fails to suppress HCC in the male STAM mice lacking insulin receptor specifically in intestinal epithelial cells (ieIRKO), which show dysbiosis and impaired gut barrier function. Furthermore, male ieIRKO mice are prone to develop HCC merely on HFD. These data suggest that impaired gut insulin signaling increases the risk of HCC, which can be countered by restoration of insulin action in diabetes.
    DOI:  https://doi.org/10.1038/s41467-023-42334-y
  24. Nat Commun. 2023 Oct 20. 14(1): 6626
    A conformation-locking inhibitor of SLC15A4 with TASL proteostatic anti-inflammatory activity.
    Andras Boeszoermenyi, Léa Bernaleau, Xudong Chen, Felix Kartnig, Min Xie, Haobo Zhang, Sensen Zhang, Maeva Delacrétaz, Anna Koren, Ann-Katrin Hopp, Vojtech Dvorak, Stefan Kubicek, Daniel Aletaha, Maojun Yang, Manuele Rebsamen, Leonhard X Heinz, Giulio Superti-Furga.
      Dysregulation of pathogen-recognition pathways of the innate immune system is associated with multiple autoimmune disorders. Due to the intricacies of the molecular network involved, the identification of pathway- and disease-specific therapeutics has been challenging. Using a phenotypic assay monitoring the degradation of the immune adapter TASL, we identify feeblin, a chemical entity which inhibits the nucleic acid-sensing TLR7/8 pathway activating IRF5 by disrupting the SLC15A4-TASL adapter module. A high-resolution cryo-EM structure of feeblin with SLC15A4 reveals that the inhibitor binds a lysosomal outward-open conformation incompatible with TASL binding on the cytoplasmic side, leading to degradation of TASL. This mechanism of action exploits a conformational switch and converts a target-binding event into proteostatic regulation of the effector protein TASL, interrupting the TLR7/8-IRF5 signaling pathway and preventing downstream proinflammatory responses. Considering that all components involved have been genetically associated with systemic lupus erythematosus and that feeblin blocks responses in disease-relevant human immune cells from patients, the study represents a proof-of-concept for the development of therapeutics against this disease.
    DOI:  https://doi.org/10.1038/s41467-023-42070-3
  25. Nat Commun. 2023 Oct 20. 14(1): 6639
    The transcription factor Zeb1 controls homeostasis and function of type 1 conventional dendritic cells.
    Yan Wang, Quan Zhang, Tingting He, Yechen Wang, Tianqi Lu, Zengge Wang, Yiyi Wang, Shen Lin, Kang Yang, Xinming Wang, Jun Xie, Ying Zhou, Yazhen Hong, Wen-Hsien Liu, Kairui Mao, Shih-Chin Cheng, Xin Chen, Qiyuan Li, Nengming Xiao.
      Type 1 conventional dendritic cells (cDC1) are the most efficient cross-presenting cells that induce protective cytotoxic T cell response. However, the regulation of their homeostasis and function is incompletely understood. Here we observe a selective reduction of splenic cDC1 accompanied by excessive cell death in mice with Zeb1 deficiency in dendritic cells, rendering the mice more resistant to Listeria infection. Additionally, cDC1 from other sources of Zeb1-deficient mice display impaired cross-presentation of exogenous antigens, compromising antitumor CD8+ T cell responses. Mechanistically, Zeb1 represses the expression of microRNA-96/182 that target Cybb mRNA of NADPH oxidase Nox2, and consequently facilitates reactive-oxygen-species-dependent rupture of phagosomal membrane to allow antigen export to the cytosol. Cybb re-expression in Zeb1-deficient cDC1 fully restores the defective cross-presentation while microRNA-96/182 overexpression in Zeb1-sufficient cDC1 inhibits cross-presentation. Therefore, our results identify a Zeb1-microRNA-96/182-Cybb pathway that controls cross-presentation in cDC1 and uncover an essential role of Zeb1 in cDC1 homeostasis.
    DOI:  https://doi.org/10.1038/s41467-023-42428-7
  26. Immunity. 2023 Oct 08. pii: S1074-7613(23)00417-X. [Epub ahead of print]
    Polyamine metabolism controls B-to-Z DNA transition to orchestrate DNA sensor cGAS activity.
    Chunyuan Zhao, Yunjin Ma, Minghui Zhang, Xiaoyan Gao, Wenbo Liang, Ying Qin, Yue Fu, Mutian Jia, Hui Song, Chengjiang Gao, Wei Zhao.
      Cyclic guanosine monophosphate (GMP)-AMP (cGAMP) synthase (cGAS) is a universal double-stranded DNA (dsDNA) sensor that recognizes foreign and self-DNA in the cytoplasm and initiates innate immune responses and has been implicated in various infectious and non-infectious contexts. cGAS binds to the backbone of dsDNA and generates the second messenger, cGAMP, which activates the stimulator of interferon genes (STING). Here, we show that the endogenous polyamines spermine and spermidine attenuated cGAS activity and innate immune responses. Mechanistically, spermine and spermidine induced the transition of B-form DNA to Z-form DNA (Z-DNA), thereby decreasing its binding affinity with cGAS. Spermidine/spermine N1-acetyltransferase 1 (SAT1), the rate-limiting enzyme in polyamine catabolism that decreases the cellular concentrations of spermine and spermidine, enhanced cGAS activation by inhibiting cellular Z-DNA accumulation; SAT1 deficiency promoted herpes simplex virus 1 (HSV-1) replication in vivo. The results indicate that spermine and spermidine induce dsDNA to adopt the Z-form conformation and that SAT1-mediated polyamine metabolism orchestrates cGAS activity.
    Keywords:  B-DNA; Z-DNA; cGAS; innate immunity; polyamine metabolism; spermidine; spermine; type I IFNs
    DOI:  https://doi.org/10.1016/j.immuni.2023.09.012
  27. Nat Commun. 2023 Oct 20. 14(1): 6635
    RING finger protein 13 protects against nonalcoholic steatohepatitis by targeting STING-relayed signaling pathways.
    Zhibin Lin, Peijun Yang, Yufeng Hu, Hao Xu, Juanli Duan, Fei He, Kefeng Dou, Lin Wang.
      Nonalcoholic fatty liver disease (NAFLD) is the most common liver disorder worldwide. Recent studies show that innate immunity-related signaling pathways fuel NAFLD progression. This study aims to identify potent regulators of innate immunity during NAFLD progression. To this end, a phenotype-based high-content screening is performed, and RING finger protein 13 (RNF13) is identified as an effective inhibitor of lipid accumulation in vitro. In vivo gain- and loss-of-function assays are conducted to investigate the role of RNF13 in NAFLD. Transcriptome sequencing and immunoprecipitation-mass spectrometry are performed to explore the underlying mechanisms. We reveal that RNF13 protein is upregulated in the liver of individuals with NASH. Rnf13 knockout in hepatocytes exacerbate insulin resistance, steatosis, inflammation, cell injury and fibrosis in the liver of diet-induced mice, which can be alleviated by Rnf13 overexpression. Mechanically, RNF13 facilitates the proteasomal degradation of stimulator of interferon genes protein (STING) in a ubiquitination-dependent way. This study provides a promising innate immunity-related target for NAFLD treatment.
    DOI:  https://doi.org/10.1038/s41467-023-42420-1
  28. Nat Chem Biol. 2023 Oct 19.
    Long-term super-resolution inner mitochondrial membrane imaging with a lipid probe.
    Shuai Zheng, Neville Dadina, Deepto Mozumdar, Lauren Lesiak, Kayli N Martinez, Evan W Miller, Alanna Schepartz.
      The inner mitochondrial membrane (IMM) generates power to drive cell function, and its dynamics control mitochondrial health and cellular homeostasis. Here, we describe the cell-permeant, lipid-like small molecule MAO-N3 and use it to assemble high-density environmentally sensitive (HIDE) probes that selectively label and image the IMM in live cells and multiple cell states. MAO-N3 pairs with strain-promoted azide-alkyne click chemistry-reactive fluorophores to support HIDE imaging using confocal, structured illumination, single-molecule localization and stimulated emission depletion microscopy, all with significantly improved resistance to photobleaching. These probes generate images with excellent spatial and temporal resolution, require no genetic manipulations, are non-toxic in model cell lines and primary cardiomyocytes (even under conditions that amplify the effects of mitochondrial toxins) and can visualize mitochondrial dynamics for 12.5 h. This probe will enable comprehensive studies of IMM dynamics with high temporal and spatial resolution.
    DOI:  https://doi.org/10.1038/s41589-023-01450-y
  29. Proc Natl Acad Sci U S A. 2023 Oct 24. 120(43): e2307203120
    Molecular mechanisms controlling the biogenesis of the TGF-β signal Vg1.
    P C Dave P Dingal, Adam N Carte, Tessa G Montague, Medel B Lim Suan, Alexander F Schier.
      The TGF-beta signals Vg1 (Dvr1/Gdf3) and Nodal form heterodimers to induce vertebrate mesendoderm. The Vg1 proprotein is a monomer retained in the endoplasmic reticulum (ER) and is processed and secreted upon heterodimerization with Nodal, but the mechanisms underlying Vg1 biogenesis are largely elusive. Here, we clarify the mechanisms underlying Vg1 retention, processing, secretion, and signaling and introduce a Synthetic Processing (SynPro) system that enables the programmed cleavage of ER-resident and extracellular proteins. First, we find that Vg1 can be processed by intra- or extracellular proteases. Second, Vg1 can be processed without Nodal but requires Nodal for secretion and signaling. Third, Vg1-Nodal signaling activity requires Vg1 processing, whereas Nodal can remain unprocessed. Fourth, Vg1 employs exposed cysteines, glycosylated asparagines, and BiP chaperone-binding motifs for monomer retention in the ER. These observations suggest two mechanisms for rapid mesendoderm induction: Chaperone-binding motifs help store Vg1 as an inactive but ready-to-heterodimerize monomer in the ER, and the flexibility of Vg1 processing location allows efficient generation of active heterodimers both intra- and extracellularly. These results establish SynPro as an in vivo processing system and define molecular mechanisms and motifs that facilitate the generation of active TGF-beta heterodimers.
    Keywords:  Nodal; Vg1; processing; retention; zebrafish
    DOI:  https://doi.org/10.1073/pnas.2307203120
  30. Nat Commun. 2023 Oct 18. 14(1): 6594
    Conserved enhancers control notochord expression of vertebrate Brachyury.
    Cassie L Kemmler, Jana Smolikova, Hannah R Moran, Brandon J Mannion, Dunja Knapp, Fabian Lim, Anna Czarkwiani, Viviana Hermosilla Aguayo, Vincent Rapp, Olivia E Fitch, Seraina Bötschi, Licia Selleri, Emma Farley, Ingo Braasch, Maximina Yun, Axel Visel, Marco Osterwalder, Christian Mosimann, Zbynek Kozmik, Alexa Burger.
      The cell type-specific expression of key transcription factors is central to development and disease. Brachyury/T/TBXT is a major transcription factor for gastrulation, tailbud patterning, and notochord formation; however, how its expression is controlled in the mammalian notochord has remained elusive. Here, we identify the complement of notochord-specific enhancers in the mammalian Brachyury/T/TBXT gene. Using transgenic assays in zebrafish, axolotl, and mouse, we discover three conserved Brachyury-controlling notochord enhancers, T3, C, and I, in human, mouse, and marsupial genomes. Acting as Brachyury-responsive, auto-regulatory shadow enhancers, in cis deletion of all three enhancers in mouse abolishes Brachyury/T/Tbxt expression selectively in the notochord, causing specific trunk and neural tube defects without gastrulation or tailbud defects. The three Brachyury-driving notochord enhancers are conserved beyond mammals in the brachyury/tbxtb loci of fishes, dating their origin to the last common ancestor of jawed vertebrates. Our data define the vertebrate enhancers for Brachyury/T/TBXTB notochord expression through an auto-regulatory mechanism that conveys robustness and adaptability as ancient basis for axis development.
    DOI:  https://doi.org/10.1038/s41467-023-42151-3
  31. Nat Commun. 2023 Oct 18. 14(1): 6535
    Clinical utility of polygenic scores for cardiometabolic disease in Arabs.
    Injeong Shim, Hiroyuki Kuwahara, NingNing Chen, Mais O Hashem, Lama AlAbdi, Mohamed Abouelhoda, Hong-Hee Won, Pradeep Natarajan, Patrick T Ellinor, Amit V Khera, Xin Gao, Fowzan S Alkuraya, Akl C Fahed.
      Arabs account for 5% of the world population and have a high burden of cardiometabolic disease, yet clinical utility of polygenic risk prediction in Arabs remains understudied. Among 5399 Arab patients, we optimize polygenic scores for 10 cardiometabolic traits, achieving a performance that is better than published scores and on par with performance in European-ancestry individuals. Odds ratio per standard deviation (OR per SD) for a type 2 diabetes score was 1.83 (95% CI 1.74-1.92), and each SD of body mass index (BMI) score was associated with 1.18 kg/m2 difference in BMI. Polygenic scores associated with disease independent of conventional risk factors, and also associated with disease severity-OR per SD for coronary artery disease (CAD) was 1.78 (95% CI 1.66-1.90) for three-vessel CAD and 1.41 (95% CI 1.29-1.53) for one-vessel CAD. We propose a pragmatic framework leveraging public data as one way to advance equitable clinical implementation of polygenic scores in non-European populations.
    DOI:  https://doi.org/10.1038/s41467-023-41985-1
  32. Nat Biomed Eng. 2023 Oct 19.
    Characterization of the responses of brain macrophages to focused ultrasound-mediated blood-brain barrier opening.
    Alina R Kline-Schoder, Sana Chintamen, Moshe J Willner, Melody R DiBenedetto, Rebecca L Noel, Alec J Batts, Nancy Kwon, Stergios Zacharoulis, Cheng-Chia Wu, Vilas Menon, Steven G Kernie, Elisa E Konofagou.
      The opening of the blood-brain barrier (BBB) by focused ultrasound (FUS) coupled with intravenously injected microbubbles can be leveraged as a form of immunotherapy for the treatment of neurodegenerative disorders. However, how FUS BBB opening affects brain macrophages is not well understood. Here by using single-cell sequencing to characterize the distinct responses of microglia and central nervous system-associated macrophages (CAMs) to FUS-mediated BBB opening in mice, we show that the treatment remodels the immune landscape via the recruitment of CAMs and the proliferation of microglia and via population size increases in disease-associated microglia. Both microglia and CAMs showed early and late increases in population sizes, yet only the proliferation of microglia increased at both timepoints. The population of disease-associated microglia also increased, accompanied by the upregulation of genes associated with gliogenesis and phagocytosis, with the depletion of brain macrophages significantly decreasing the duration of BBB opening.
    DOI:  https://doi.org/10.1038/s41551-023-01107-0
  33. Nat Biomed Eng. 2023 Oct 16.
    Fluorescence lifetime of injected indocyanine green as a universal marker of solid tumours in patients.
    Rahul Pal, Thinzar M Lwin, Murali Krishnamoorthy, Hannah R Collins, Corey D Chan, Andrey Prilutskiy, MacLean P Nasrallah, Tom H Dijkhuis, Shriya Shukla, Amy L Kendall, Michael S Marshall, Stefan A Carp, Yin P Hung, Angela R Shih, Maria Martinez-Lage, Lawrence Zukerberg, Peter M Sadow, William C Faquin, Brian V Nahed, Allen L Feng, Kevin S Emerick, J Sven D Mieog, Alexander L Vahrmeijer, Karthik Rajasekaran, John Y K Lee, Kenneth S Rankin, Santiago Lozano-Calderon, Mark A Varvares, Kenneth K Tanabe, Anand T N Kumar.
      The surgical resection of solid tumours can be enhanced by fluorescence-guided imaging. However, variable tumour uptake and incomplete clearance of fluorescent dyes reduces the accuracy of distinguishing tumour from normal tissue via conventional fluorescence intensity-based imaging. Here we show that, after systemic injection of the near-infrared dye indocyanine green in patients with various types of solid tumour, the fluorescence lifetime (FLT) of tumour tissue is longer than the FLT of non-cancerous tissue. This tumour-specific shift in FLT can be used to distinguish tumours from normal tissue with an accuracy of over 97% across tumour types, and can be visualized at the cellular level using microscopy and in larger specimens through wide-field imaging. Unlike fluorescence intensity, which depends on imaging-system parameters, tissue depth and the amount of dye taken up by tumours, FLT is a photophysical property that is largely independent of these factors. FLT imaging with indocyanine green may improve the accuracy of cancer surgeries.
    DOI:  https://doi.org/10.1038/s41551-023-01105-2
  34. Nat Microbiol. 2023 Oct 19.
    Bacterial histones unveiled.
    Bibhusita Pani, Evgeny Nudler.
      
    DOI:  https://doi.org/10.1038/s41564-023-01509-5
  35. Nat Commun. 2023 Oct 18. 14(1): 6597
    A spatial sequencing atlas of age-induced changes in the lung during influenza infection.
    Moujtaba Y Kasmani, Paytsar Topchyan, Ashley K Brown, Ryan J Brown, Xiaopeng Wu, Yao Chen, Achia Khatun, Donia Alson, Yue Wu, Robert Burns, Chien-Wei Lin, Matthew R Kudek, Jie Sun, Weiguo Cui.
      Influenza virus infection causes increased morbidity and mortality in the elderly. Aging impairs the immune response to influenza, both intrinsically and because of altered interactions with endothelial and pulmonary epithelial cells. To characterize these changes, we performed single-cell RNA sequencing (scRNA-seq), spatial transcriptomics, and bulk RNA sequencing (bulk RNA-seq) on lung tissue from young and aged female mice at days 0, 3, and 9 post-influenza infection. Our analyses identified dozens of key genes differentially expressed in kinetic, age-dependent, and cell type-specific manners. Aged immune cells exhibited altered inflammatory, memory, and chemotactic profiles. Aged endothelial cells demonstrated characteristics of reduced vascular wound healing and a prothrombotic state. Spatial transcriptomics identified novel profibrotic and antifibrotic markers expressed by epithelial and non-epithelial cells, highlighting the complex networks that promote fibrosis in aged lungs. Bulk RNA-seq generated a timeline of global transcriptional activity, showing increased expression of genes involved in inflammation and coagulation in aged lungs. Our work provides an atlas of high-throughput sequencing methodologies that can be used to investigate age-related changes in the response to influenza virus, identify novel cell-cell interactions for further study, and ultimately uncover potential therapeutic targets to improve health outcomes in the elderly following influenza infection.
    DOI:  https://doi.org/10.1038/s41467-023-42021-y
  36. J Clin Invest. 2023 Oct 19. pii: e168314. [Epub ahead of print]
    A20 regulates lymphocyte adhesion in murine neuroinflammation by restricting endothelial ICOSL expression in the CNS.
    Lisa Johann, Sasha Soldati, Kristin Müller, Josephine Lampe, Federico Marini, Matthias Klein, Eva Schramm, Nathalie Ries, Carsten Schelmbauer, Ilaria Palagi, Khalad Karram, Julian C Assmann, Mahtab A Khan, Jan Wenzel, Mirko Hh Schmidt, Jakob Körbelin, Dirk Schlüter, Geert van Loo, Tobias Bopp, Britta Engelhardt, Markus Schwaninger, Ari Waisman.
      A20 is a ubiquitin-modifying protein that negatively regulates NF-κB signaling. Mutations in A20/TNFAIP3 are associated with a variety of autoimmune diseases, including multiple sclerosis (MS). We found that deletion of A20 in central nervous system (CNS) endothelial cells (ECs) enhances experimental autoimmune encephalomyelitis (EAE), a mouse model of MS. A20∆CNS-EC mice showed increased numbers of CNS-infiltrating immune cells during neuroinflammation and in the steady state. While the integrity of the blood-brain barrier (BBB) was not impaired, we observed a strong activation of CNS-ECs in these mice, with dramatically increased levels of the adhesion molecules ICAM-1 and VCAM-1. We discovered ICOSL as adhesion molecule expressed by A20-deficient CNS-ECs. Silencing of ICOSL in CNS microvascular ECs partly reversed the phenotype of A20∆CNS-EC mice without reaching statistical significance and delayed the onset of EAE symptoms in wildtype mice. In addition, blocking of ICOSL on primary mouse brain microvascular endothelial cells (pMBMECs) impaired the adhesion of T cells in vitro. Taken together, we here propose that CNS EC-ICOSL contributes to the firm adhesion of T cells to the BBB, promoting their entry into the CNS and eventually driving neuroinflammation.
    Keywords:  Autoimmunity; Endothelial cells; Mouse models; Multiple sclerosis; Neuroscience
    DOI:  https://doi.org/10.1172/JCI168314
  37. Nat Cell Biol. 2023 Oct 19.
    A Legionella toxin exhibits tRNA mimicry and glycosyl transferase activity to target the translation machinery and trigger a ribotoxic stress response.
    Advait Subramanian, Lan Wang, Tom Moss, Mark Voorhies, Smriti Sangwan, Erica Stevenson, Ernst H Pulido, Samentha Kwok, Robert J Chalkley, Kathy H Li, Nevan J Krogan, Danielle L Swaney, Alma L Burlingame, Stephen N Floor, Anita Sil, Peter Walter, Shaeri Mukherjee.
      A widespread strategy employed by pathogens to establish infection is to inhibit host-cell protein synthesis. Legionella pneumophila, an intracellular bacterial pathogen and the causative organism of Legionnaires' disease, secretes a subset of protein effectors into host cells that inhibit translation elongation. Mechanistic insights into how the bacterium targets translation elongation remain poorly defined. We report here that the Legionella effector SidI functions in an unprecedented way as a transfer-RNA mimic that directly binds to and glycosylates the ribosome. The 3.1 Å cryo-electron microscopy structure of SidI reveals an N-terminal domain with an 'inverted L' shape and surface-charge distribution characteristic of tRNA mimicry, and a C-terminal domain that adopts a glycosyl transferase fold that licenses SidI to utilize GDP-mannose as a sugar precursor. This coupling of tRNA mimicry and enzymatic action endows SidI with the ability to block protein synthesis with a potency comparable to ricin, one of the most powerful toxins known. In Legionella-infected cells, the translational pausing activated by SidI elicits a stress response signature mimicking the ribotoxic stress response, which is activated by elongation inhibitors that induce ribosome collisions. SidI-mediated effects on the ribosome activate the stress kinases ZAKα and p38, which in turn drive an accumulation of the protein activating transcription factor 3 (ATF3). Intriguingly, ATF3 escapes the translation block imposed by SidI, translocates to the nucleus and orchestrates the transcription of stress-inducible genes that promote cell death, revealing a major role for ATF3 in the response to collided ribosome stress. Together, our findings elucidate a novel mechanism by which a pathogenic bacterium employs tRNA mimicry to hijack a ribosome-to-nuclear signalling pathway that regulates cell fate.
    DOI:  https://doi.org/10.1038/s41556-023-01248-z
  38. Cell Stem Cell. 2023 Oct 16. pii: S1934-5909(23)00358-2. [Epub ahead of print]
    SRCAP mutations drive clonal hematopoiesis through epigenetic and DNA repair dysregulation.
    Chun-Wei Chen, Linda Zhang, Ravi Dutta, Abhishek Niroula, Peter G Miller, Christopher J Gibson, Alexander G Bick, Jaime M Reyes, Yi-Tang Lee, Ayala Tovy, Tianpeng Gu, Sarah Waldvogel, Yi-Hung Chen, Bryan J Venters, Pierre-Olivier Estève, Sriharsa Pradhan, Michael-Christopher Keogh, Pradeep Natarajan, Koichi Takahashi, Adam S Sperling, Margaret A Goodell.
      Somatic mutations accumulate in all cells with age and can confer a selective advantage, leading to clonal expansion over time. In hematopoietic cells, mutations in a subset of genes regulating DNA repair or epigenetics frequently lead to clonal hematopoiesis (CH). Here, we describe the context and mechanisms that lead to enrichment of hematopoietic stem cells (HSCs) with mutations in SRCAP, which encodes a chromatin remodeler that also influences DNA repair. We show that SRCAP mutations confer a selective advantage in human cells and in mice upon treatment with the anthracycline-class chemotherapeutic doxorubicin and bone marrow transplantation. Furthermore, Srcap mutations lead to a lymphoid-biased expansion, driven by loss of SRCAP-regulated H2A.Z deposition and increased DNA repair. Altogether, we demonstrate that SRCAP operates at the intersection of multiple pathways in stem and progenitor cells, offering a new perspective on the functional impact of genetic variants that promote stem cell competition in the hematopoietic system.
    Keywords:  DNA damage; H2A.Z; SRCAP; chromatin remodeling; clonal hematopoiesis; hematopoietic stem cells; lymphoid
    DOI:  https://doi.org/10.1016/j.stem.2023.09.011
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