bims-nimamd Biomed News
on Neuroimmunity and neuroinflammation in ageing and metabolic disease
Issue of 2024‒03‒10
48 papers selected by
Fawaz Alzaïd, Sorbonne Université
  1. Writing my ticket.
  2. Slowing human neurons.
  3. Deficiency of ASGR1 promotes liver injury by increasing GP73-mediated hepatic endoplasmic reticulum stress.
  4. A Treg cell duo for VAT control.
  5. Multi-ancestry polygenic mechanisms of type 2 diabetes.
  6. Non-coding autoimmune risk variant defines role for ICOS in T peripheral helper cell development.
  7. High-density volumetric super-resolution microscopy.
  8. Kdm1a safeguards the topological boundaries of PRC2-repressed genes and prevents aging-related euchromatinization in neurons.
  9. Adipose Tissue Peroxisomal Lipid Synthesis Orchestrates Obesity and Insulin Resistance through LXR-Dependent Lipogenesis.
  10. A spatially-resolved transcriptional atlas of the murine dorsal pons at single-cell resolution.
  11. Growing early career researchers pathways through co-review.
  12. Learning with baby.
  13. Neuronal miR-9 promotes HSV-1 epigenetic silencing and latency by repressing Oct-1 and Onecut family genes.
  14. NDUFS4 regulates cristae remodeling in diabetic kidney disease.
  15. PRMT5 Promotes T follicular helper Cell Differentiation and Germinal Center Responses during Influenza Virus Infection.
  16. microRNA-33 controls hunger signaling in hypothalamic AgRP neurons.
  17. Centrosome amplification and aneuploidy driven by the HIV-1-induced Vpr•VprBP•Plk4 complex in CD4+ T cells.
  18. Decoding chromatin states by proteomic profiling of nucleosome readers.
  19. Key homeobox transcription factors regulate the development of the firefly's adult light organ and bioluminescence.
  20. Sex-specific genetic architecture of blood pressure.
  21. Site-specific regulation of Th2 differentiation within lymph node microenvironments.
  22. Interactions between immune cells recorded.
  23. A humanized mouse model for adeno-associated viral gene therapy.
  24. Transmembrane domain-driven PD-1 dimers mediate T cell inhibition.
  25. Carnosine facilitates lysosomal release of inhibitors of T cell surveillance.
  26. Inactivation of cytidine triphosphate synthase 1 prevents fatal auto-immunity in mice.
  27. WIPI4 loss linked to ferroptosis.
  28. Sustained AhR activity programs memory fate of early effector CD8+ T cells.
  29. Tuning of plasma cell lifespan by competition explains the longevity and heterogeneity of antibody persistence.
  30. Chloride intracellular channel (CLIC) proteins function as fusogens.
  31. The eyes have it.
  32. Spatially-resolved transcriptomics reveal macrophage heterogeneity and prognostic significance in diffuse large B-cell lymphoma.
  33. BHLHE40/41 regulate microglia and peripheral macrophage responses associated with Alzheimer's disease and other disorders of lipid-rich tissues.
  34. Lipid droplets and cellular lipid flux.
  35. Structural basis for self-discrimination by neoantigen-specific TCRs.
  36. MYC activity at enhancers drives prognostic transcriptional programs through an epigenetic switch.
  37. Hypothalamic astrocyte NAD+ salvage pathway mediates the coupling of dietary fat overconsumption in a mouse model of obesity.
  38. Cholesterol 25-hydroxylase mediates neuroinflammation and neurodegeneration in a mouse model of tauopathy.
  39. Pla2g12b drives expansion of triglyceride-rich lipoproteins.
  40. ALKBH5-mediated m6A modification of IL-11 drives macrophage-to-myofibroblast transition and pathological cardiac fibrosis in mice.
  41. RHBDL4-triggered downregulation of COPII adaptor protein TMED7 suppresses TLR4-mediated inflammatory signaling.
  42. SAM68 directs STING signaling to apoptosis in macrophages.
  43. Genome-wide characterization of circulating metabolic biomarkers.
  44. Sister chromatid cohesion is mediated by individual cohesin complexes.
  45. Severely polarized extracellular acidity around tumour cells.
  46. Roger Guillemin (1924-2024), neuroscientist who showed how the brain controls hormones.
  47. Age-related ciliopathy: Obesogenic shortening of melanocortin-4 receptor-bearing neuronal primary cilia.
  48. Genetic architecture of the structural connectome.
  1. Science. 2024 Mar 08. 383(6687): 1150
    Writing my ticket.
    Violeta J Rodriguez.
      
    DOI:  https://doi.org/10.1126/science.ado9936
  2. Nat Neurosci. 2024 Mar;27(3): 390
    Slowing human neurons.
    Shari Wiseman.
      
    DOI:  https://doi.org/10.1038/s41593-024-01602-w
  3. Nat Commun. 2024 Mar 08. 15(1): 1908
    Deficiency of ASGR1 promotes liver injury by increasing GP73-mediated hepatic endoplasmic reticulum stress.
    Zhe Zhang, Xiang Kai Leng, Yuan Yuan Zhai, Xiao Zhang, Zhi Wei Sun, Jun Ying Xiao, Jun Feng Lu, Kun Liu, Bo Xia, Qi Gao, Miao Jia, Cheng Qi Xu, Yi Na Jiang, Xiao Gang Zhang, Kai Shan Tao, Jiang Wei Wu.
      Liver injury is a core pathological process in the majority of liver diseases, yet the genetic factors predisposing individuals to its initiation and progression remain poorly understood. Here we show that asialoglycoprotein receptor 1 (ASGR1), a lectin specifically expressed in the liver, is downregulated in patients with liver fibrosis or cirrhosis and male mice with liver injury. ASGR1 deficiency exacerbates while its overexpression mitigates acetaminophen-induced acute and CCl4-induced chronic liver injuries in male mice. Mechanistically, ASGR1 binds to an endoplasmic reticulum stress mediator GP73 and facilitates its lysosomal degradation. ASGR1 depletion increases circulating GP73 levels and promotes the interaction between GP73 and BIP to activate endoplasmic reticulum stress, leading to liver injury. Neutralization of GP73 not only attenuates ASGR1 deficiency-induced liver injuries but also improves survival in mice received a lethal dose of acetaminophen. Collectively, these findings identify ASGR1 as a potential genetic determinant of susceptibility to liver injury and propose it as a therapeutic target for the treatment of liver injury.
    DOI:  https://doi.org/10.1038/s41467-024-46135-9
  4. Nat Rev Immunol. 2024 Mar 08.
    A Treg cell duo for VAT control.
    Maria Papatriantafyllou.
      
    DOI:  https://doi.org/10.1038/s41577-024-01018-4
  5. Nat Med. 2024 Mar 05.
    Multi-ancestry polygenic mechanisms of type 2 diabetes.
    Kirk Smith, Aaron J Deutsch, Carolyn McGrail, Hyunkyung Kim, Sarah Hsu, Alicia Huerta-Chagoya, Ravi Mandla, Philip H Schroeder, Kenneth E Westerman, Lukasz Szczerbinski, Timothy D Majarian, Varinderpal Kaur, Alice Williamson, Noah Zaitlen, Melina Claussnitzer, Jose C Florez, Alisa K Manning, Josep M Mercader, Kyle J Gaulton, Miriam S Udler.
      Type 2 diabetes (T2D) is a multifactorial disease with substantial genetic risk, for which the underlying biological mechanisms are not fully understood. In this study, we identified multi-ancestry T2D genetic clusters by analyzing genetic data from diverse populations in 37 published T2D genome-wide association studies representing more than 1.4 million individuals. We implemented soft clustering with 650 T2D-associated genetic variants and 110 T2D-related traits, capturing known and novel T2D clusters with distinct cardiometabolic trait associations across two independent biobanks representing diverse genetic ancestral populations (African, n = 21,906; Admixed American, n = 14,410; East Asian, n =2,422; European, n = 90,093; and South Asian, n = 1,262). The 12 genetic clusters were enriched for specific single-cell regulatory regions. Several of the polygenic scores derived from the clusters differed in distribution among ancestry groups, including a significantly higher proportion of lipodystrophy-related polygenic risk in East Asian ancestry. T2D risk was equivalent at a body mass index (BMI) of 30 kg m-2 in the European subpopulation and 24.2 (22.9-25.5) kg m-2 in the East Asian subpopulation; after adjusting for cluster-specific genetic risk, the equivalent BMI threshold increased to 28.5 (27.1-30.0) kg m-2 in the East Asian group. Thus, these multi-ancestry T2D genetic clusters encompass a broader range of biological mechanisms and provide preliminary insights to explain ancestry-associated differences in T2D risk profiles.
    DOI:  https://doi.org/10.1038/s41591-024-02865-3
  6. Nat Commun. 2024 Mar 09. 15(1): 2150
    Non-coding autoimmune risk variant defines role for ICOS in T peripheral helper cell development.
    Taehyeung Kim, Marta Martínez-Bonet, Qiang Wang, Nicolaj Hackert, Jeffrey A Sparks, Yuriy Baglaenko, Byunghee Koh, Roxane Darbousset, Raquel Laza-Briviesca, Xiaoting Chen, Vitor R C Aguiar, Darren J Chiu, Harm-Jan Westra, Maria Gutierrez-Arcelus, Matthew T Weirauch, Soumya Raychaudhuri, Deepak A Rao, Peter A Nigrovic.
      Fine-mapping and functional studies implicate rs117701653, a non-coding single nucleotide polymorphism in the CD28/CTLA4/ICOS locus, as a risk variant for rheumatoid arthritis and type 1 diabetes. Here, using DNA pulldown, mass spectrometry, genome editing and eQTL analysis, we establish that the disease-associated risk allele is functional, reducing affinity for the inhibitory chromosomal regulator SMCHD1 to enhance expression of inducible T-cell costimulator (ICOS) in memory CD4+ T cells from healthy donors. Higher ICOS expression is paralleled by an increase in circulating T peripheral helper (Tph) cells and, in rheumatoid arthritis patients, of blood and joint fluid Tph cells as well as circulating plasmablasts. Correspondingly, ICOS ligation and carriage of the rs117701653 risk allele accelerate T cell differentiation into CXCR5-PD-1high Tph cells producing IL-21 and CXCL13. Thus, mechanistic dissection of a functional non-coding variant in human autoimmunity discloses a previously undefined pathway through which ICOS regulates Tph development and abundance.
    DOI:  https://doi.org/10.1038/s41467-024-46457-8
  7. Nat Commun. 2024 Mar 02. 15(1): 1940
    High-density volumetric super-resolution microscopy.
    Sam Daly, João Ferreira Fernandes, Ezra Bruggeman, Anoushka Handa, Ruby Peters, Sarah Benaissa, Boya Zhang, Joseph S Beckwith, Edward W Sanders, Ruth R Sims, David Klenerman, Simon J Davis, Kevin O'Holleran, Steven F Lee.
      Volumetric super-resolution microscopy typically encodes the 3D position of single-molecule fluorescence into a 2D image by changing the shape of the point spread function (PSF) as a function of depth. However, the resulting large and complex PSF spatial footprints reduce biological throughput and applicability by requiring lower labeling densities to avoid overlapping fluorescent signals. We quantitatively compare the density dependence of single-molecule light field microscopy (SMLFM) to other 3D PSFs (astigmatism, double helix and tetrapod) showing that SMLFM enables an order-of-magnitude speed improvement compared to the double helix PSF by resolving overlapping emitters through parallax. We demonstrate this optical robustness experimentally with high accuracy ( > 99.2 ± 0.1%, 0.1 locs μm-2) and sensitivity ( > 86.6 ± 0.9%, 0.1 locs μm-2) through whole-cell (scan-free) imaging and tracking of single membrane proteins in live primary B cells. We also exemplify high-density volumetric imaging (0.15 locs μm-2) in dense cytosolic tubulin datasets.
    DOI:  https://doi.org/10.1038/s41467-024-45828-5
  8. Nat Commun. 2024 Mar 07. 15(1): 1781
    Kdm1a safeguards the topological boundaries of PRC2-repressed genes and prevents aging-related euchromatinization in neurons.
    Beatriz Del Blanco, Sergio Niñerola, Ana M Martín-González, Juan Paraíso-Luna, Minji Kim, Rafael Muñoz-Viana, Carina Racovac, Jose V Sanchez-Mut, Yijun Ruan, Ángel Barco.
      Kdm1a is a histone demethylase linked to intellectual disability with essential roles during gastrulation and the terminal differentiation of specialized cell types, including neurons, that remains highly expressed in the adult brain. To explore Kdm1a's function in adult neurons, we develop inducible and forebrain-restricted Kdm1a knockouts. By applying multi-omic transcriptome, epigenome and chromatin conformation data, combined with super-resolution microscopy, we find that Kdm1a elimination causes the neuronal activation of nonneuronal genes that are silenced by the polycomb repressor complex and interspersed with active genes. Functional assays demonstrate that the N-terminus of Kdm1a contains an intrinsically disordered region that is essential to segregate Kdm1a-repressed genes from the neighboring active chromatin environment. Finally, we show that the segregation of Kdm1a-target genes is weakened in neurons during natural aging, underscoring the role of Kdm1a safeguarding neuronal genome organization and gene silencing throughout life.
    DOI:  https://doi.org/10.1038/s41467-024-45773-3
  9. Mol Metab. 2024 Mar 06. pii: S2212-8778(24)00044-9. [Epub ahead of print] 101913
    Adipose Tissue Peroxisomal Lipid Synthesis Orchestrates Obesity and Insulin Resistance through LXR-Dependent Lipogenesis.
    Brian Kleiboeker, Anyuan He, Min Tan, Dongliang Lu, Donghua Hu, Xuejing Liu, Parniyan Goodarzi, Fong-Fu Hsu, Babak Razani, Clay F Semenkovich, Irfan J Lodhi.
      Adipose tissue mass is maintained by a balance between lipolysis and lipid storage. The contribution of adipose lipogenesis to fat mass, especially in the setting of high-fat feeding, is considered minor. Here, we report that adipose-specific knockout of the peroxisomal lipid synthetic protein PexRAP promotes diet-induced obesity and insulin resistance through activation of de novo lipogenesis. PexRAP inactivation inhibits the flux of carbons to ethanolamine plasmalogens. This increases nuclear PC/PE ratio and promotes cholesterol mislocalization, resulting in the activation of liver X receptor (LXR), a nuclear receptor known to be activated by increased intracellular cholesterol. LXR activation leads to increased expression of the phospholipid remodeling enzyme LPCAT3 and induces fatty acid synthase-mediated lipogenesis, which promotes diet-induced obesity and insulin resistance. Treatment of PexRAP-deficient adipocytes with alkylglycerol, a plasmalogen precursor that enters the synthetic pathway downstream of PexRAP, rescues nuclear cholesterol mislocalization and LXR activation. These studies reveal an unexpected role for peroxisome-derived lipids in regulating LXR-dependent lipogenesis and suggest that activation of lipogenesis, combined with dietary lipid overload, exacerbates obesity and metabolic dysregulation.
    DOI:  https://doi.org/10.1016/j.molmet.2024.101913
  10. Nat Commun. 2024 Mar 04. 15(1): 1966
    A spatially-resolved transcriptional atlas of the murine dorsal pons at single-cell resolution.
    Stefano Nardone, Roberto De Luca, Antonino Zito, Nataliya Klymko, Dimitris Nicoloutsopoulos, Oren Amsalem, Cory Brannigan, Jon M Resch, Christopher L Jacobs, Deepti Pant, Molly Veregge, Harini Srinivasan, Ryan M Grippo, Zongfang Yang, Mark L Zeidel, Mark L Andermann, Kenneth D Harris, Linus T Tsai, Elda Arrigoni, Anne M J Verstegen, Clifford B Saper, Bradford B Lowell.
      The "dorsal pons", or "dorsal pontine tegmentum" (dPnTg), is part of the brainstem. It is a complex, densely packed region whose nuclei are involved in regulating many vital functions. Notable among them are the parabrachial nucleus, the Kölliker Fuse, the Barrington nucleus, the locus coeruleus, and the dorsal, laterodorsal, and ventral tegmental nuclei. In this study, we applied single-nucleus RNA-seq (snRNA-seq) to resolve neuronal subtypes based on their unique transcriptional profiles and then used multiplexed error robust fluorescence in situ hybridization (MERFISH) to map them spatially. We sampled ~1 million cells across the dPnTg and defined the spatial distribution of over 120 neuronal subtypes. Our analysis identified an unpredicted high transcriptional diversity in this region and pinpointed the unique marker genes of many neuronal subtypes. We also demonstrated that many neuronal subtypes are transcriptionally similar between humans and mice, enhancing this study's translational value. Finally, we developed a freely accessible, GPU and CPU-powered dashboard ( http://harvard.heavy.ai:6273/ ) that combines interactive visual analytics and hardware-accelerated SQL into a data science framework to allow the scientific community to query and gain insights into the data.
    DOI:  https://doi.org/10.1038/s41467-024-45907-7
  11. Nat Commun. 2024 Mar 05. 15(1): 1869
    Growing early career researchers pathways through co-review.
      
    DOI:  https://doi.org/10.1038/s41467-024-45269-0
  12. Nat Neurosci. 2024 Mar;27(3): 390
    Learning with baby.
    Rebecca Wright.
      
    DOI:  https://doi.org/10.1038/s41593-024-01603-9
  13. Nat Commun. 2024 Mar 05. 15(1): 1991
    Neuronal miR-9 promotes HSV-1 epigenetic silencing and latency by repressing Oct-1 and Onecut family genes.
    Yue Deng, Yuqi Lin, Siyu Chen, Yuhang Xiang, Hongjia Chen, Shuyuan Qi, Hyung Suk Oh, Biswajit Das, Gloria Komazin-Meredith, Jean M Pesola, David M Knipe, Donald M Coen, Dongli Pan.
      Herpes simplex virus 1 (HSV-1) latent infection entails repression of viral lytic genes in neurons. By functional screening using luciferase-expressing HSV-1, we identify ten neuron-specific microRNAs potentially repressing HSV-1 neuronal replication. Transfection of miR-9, the most active candidate from the screen, decreases HSV-1 replication and gene expression in Neuro-2a cells. Ectopic expression of miR-9 from lentivirus or recombinant HSV-1 suppresses HSV-1 replication in male primary mouse neurons in culture and mouse trigeminal ganglia in vivo, and reactivation from latency in the primary neurons. Target prediction and validation identify transcription factors Oct-1, a known co-activator of HSV transcription, and all three Onecut family members as miR-9 targets. Knockdown of ONECUT2 decreases HSV-1 yields in Neuro-2a cells. Overexpression of each ONECUT protein increases HSV-1 replication in Neuro-2a cells, human induced pluripotent stem cell-derived neurons, and primary mouse neurons, and accelerates reactivation from latency in the mouse neurons. Mutagenesis, ChIP-seq, RNA-seq, ChIP-qPCR and ATAC-seq results suggest that ONECUT2 can nonspecifically bind to viral genes via its CUT domain, globally stimulate viral gene transcription, reduce viral heterochromatin and enhance the accessibility of viral chromatin. Thus, neuronal miR-9 promotes viral epigenetic silencing and latency by targeting multiple host transcription factors important for lytic gene activation.
    DOI:  https://doi.org/10.1038/s41467-024-46057-6
  14. Nat Commun. 2024 Mar 04. 15(1): 1965
    NDUFS4 regulates cristae remodeling in diabetic kidney disease.
    Koki Mise, Jianyin Long, Daniel L Galvan, Zengchun Ye, Guizhen Fan, Rajesh Sharma, Irina I Serysheva, Travis I Moore, Collene R Jeter, M Anna Zal, Motoo Araki, Jun Wada, Paul T Schumacker, Benny H Chang, Farhad R Danesh.
      The mitochondrial electron transport chain (ETC) is a highly adaptive process to meet metabolic demands of the cell, and its dysregulation has been associated with diverse clinical pathologies. However, the role and nature of impaired ETC in kidney diseases remains poorly understood. Here, we generate diabetic mice with podocyte-specific overexpression of Ndufs4, an accessory subunit of mitochondrial complex I, as a model investigate the role of ETC integrity in diabetic kidney disease (DKD). We find that conditional male mice with genetic overexpression of Ndufs4 exhibit significant improvements in cristae morphology, mitochondrial dynamics, and albuminuria. By coupling proximity labeling with super-resolution imaging, we also identify the role of cristae shaping protein STOML2 in linking NDUFS4 with improved cristae morphology. Together, we provide the evidence on the central role of NDUFS4 as a regulator of cristae remodeling and mitochondrial function in kidney podocytes. We propose that targeting NDUFS4 represents a promising approach to slow the progression of DKD.
    DOI:  https://doi.org/10.1038/s41467-024-46366-w
  15. J Immunol. 2024 Mar 04. pii: ji2300270. [Epub ahead of print]
    PRMT5 Promotes T follicular helper Cell Differentiation and Germinal Center Responses during Influenza Virus Infection.
    Kaitlin A Read, Stephanie A Amici, Sadaf Farsi, Madeline Cutcliffe, Bella Lee, Chan-Wang Jerry Lio, Hsin-Jung Joyce Wu, Mireia Guerau-de-Arellano, Kenneth J Oestreich.
      Protein arginine methyltransferases (PRMTs) modify diverse protein targets and regulate numerous cellular processes; yet, their contributions to individual effector T cell responses during infections are incompletely understood. In this study, we identify PRMT5 as a critical regulator of CD4+ T follicular helper cell (Tfh) responses during influenza virus infection in mice. Conditional PRMT5 deletion in murine T cells results in an almost complete ablation of both Tfh and T follicular regulatory populations and, consequently, reduced B cell activation and influenza-specific Ab production. Supporting a potential mechanism, we observe elevated surface expression of IL-2Rα on non-T regulatory effector PRMT5-deficient T cells. Notably, IL-2 signaling is known to negatively impact Tfh differentiation. Collectively, our findings identify PRMT5 as a prominent regulator of Tfh programming, with potential causal links to IL-2 signaling.
    DOI:  https://doi.org/10.4049/jimmunol.2300270
  16. Nat Commun. 2024 Mar 08. 15(1): 2131
    microRNA-33 controls hunger signaling in hypothalamic AgRP neurons.
    Nathan L Price, Pablo Fernández-Tussy, Luis Varela, Magdalena P Cardelo, Marya Shanabrough, Binod Aryal, Rafael de Cabo, Yajaira Suárez, Tamas L Horvath, Carlos Fernández-Hernando.
      AgRP neurons drive hunger, and excessive nutrient intake is the primary driver of obesity and associated metabolic disorders. While many factors impacting central regulation of feeding behavior have been established, the role of microRNAs in this process is poorly understood. Utilizing unique mouse models, we demonstrate that miR-33 plays a critical role in the regulation of AgRP neurons, and that loss of miR-33 leads to increased feeding, obesity, and metabolic dysfunction in mice. These effects include the regulation of multiple miR-33 target genes involved in mitochondrial biogenesis and fatty acid metabolism. Our findings elucidate a key regulatory pathway regulated by a non-coding RNA that impacts hunger by controlling multiple bioenergetic processes associated with the activation of AgRP neurons, providing alternative therapeutic approaches to modulate feeding behavior and associated metabolic diseases.
    DOI:  https://doi.org/10.1038/s41467-024-46427-0
  17. Nat Commun. 2024 Mar 05. 15(1): 2017
    Centrosome amplification and aneuploidy driven by the HIV-1-induced Vpr•VprBP•Plk4 complex in CD4+ T cells.
    Jung-Eun Park, Tae-Sung Kim, Yan Zeng, Melissa Mikolaj, Jong Il Ahn, Muhammad S Alam, Christina M Monnie, Victoria Shi, Ming Zhou, Tae-Wook Chun, Frank Maldarelli, Kedar Narayan, Jinwoo Ahn, Jonathan D Ashwell, Klaus Strebel, Kyung S Lee.
      HIV-1 infection elevates the risk of developing various cancers, including T-cell lymphoma. Whether HIV-1-encoded proteins directly contribute to oncogenesis remains unknown. We observe that approximately 1-5% of CD4+ T cells from the blood of people living with HIV-1 exhibit over-duplicated centrioles, suggesting that centrosome amplification underlies the development of HIV-1-associated cancers by driving aneuploidy. Through affinity purification, biochemical, and cellular analyses, we discover that Vpr, an accessory protein of HIV-1, hijacks the centriole duplication machinery and induces centrosome amplification and aneuploidy. Mechanistically, Vpr forms a cooperative ternary complex with an E3 ligase subunit, VprBP, and polo-like kinase 4 (Plk4). Unexpectedly, however, the complex enhances Plk4's functionality by promoting its relocalization to the procentriole assembly and induces centrosome amplification. Loss of either Vpr's C-terminal 17 residues or VprBP acidic region, the two elements required for binding to Plk4 cryptic polo-box, abrogates Vpr's capacity to induce these events. Furthermore, HIV-1 WT, but not its Vpr mutant, induces multiple centrosomes and aneuploidy in human primary CD4+ T cells. We propose that the Vpr•VprBP•Plk4 complex serves as a molecular link that connects HIV-1 infection to oncogenesis and that inhibiting the Vpr C-terminal motif may reduce the occurrence of HIV-1-associated cancers.
    DOI:  https://doi.org/10.1038/s41467-024-46306-8
  18. Nature. 2024 Mar 06.
    Decoding chromatin states by proteomic profiling of nucleosome readers.
    Saulius Lukauskas, Andrey Tvardovskiy, Nhuong V Nguyen, Mara Stadler, Peter Faull, Tina Ravnsborg, Bihter Özdemir Aygenli, Scarlett Dornauer, Helen Flynn, Rik G H Lindeboom, Teresa K Barth, Kevin Brockers, Stefanie M Hauck, Michiel Vermeulen, Ambrosius P Snijders, Christian L Müller, Peter A DiMaggio, Ole N Jensen, Robert Schneider, Till Bartke.
      DNA and histone modifications combine into characteristic patterns that demarcate functional regions of the genome1,2. While many 'readers' of individual modifications have been described3-5, how chromatin states comprising composite modification signatures, histone variants and internucleosomal linker DNA are interpreted is a major open question. Here we use a multidimensional proteomics strategy to systematically examine the interaction of around 2,000 nuclear proteins with over 80 modified dinucleosomes representing promoter, enhancer and heterochromatin states. By deconvoluting complex nucleosome-binding profiles into networks of co-regulated proteins and distinct nucleosomal features driving protein recruitment or exclusion, we show comprehensively how chromatin states are decoded by chromatin readers. We find highly distinctive binding responses to different features, many factors that recognize multiple features, and that nucleosomal modifications and linker DNA operate largely independently in regulating protein binding to chromatin. Our online resource, the Modification Atlas of Regulation by Chromatin States (MARCS), provides in-depth analysis tools to engage with our results and advance the discovery of fundamental principles of genome regulation by chromatin states.
    DOI:  https://doi.org/10.1038/s41586-024-07141-5
  19. Nat Commun. 2024 Mar 05. 15(1): 1736
    Key homeobox transcription factors regulate the development of the firefly's adult light organ and bioluminescence.
    Xinhua Fu, Xinlei Zhu.
      Adult fireflies exhibit unique flashing courtship signals, emitted by specialized light organs, which develop mostly independently from larval light organs during the pupal stage. The mechanisms of adult light organ development have not been thoroughly studied until now. Here we show that key homeobox transcription factors AlABD-B and AlUNC-4 regulate the development of adult light organs and bioluminescence in the firefly Aquatica leii. Interference with the expression of AlAbd-B and AlUnc-4 genes results in undeveloped or non-luminescent adult light organs. AlABD-B regulates AlUnc-4, and they interact with each other. AlABD-B and AlUNC-4 activate the expression of the luciferase gene AlLuc1 and some peroxins. Four peroxins are involved in the import of AlLUC1 into peroxisomes. Our study provides key insights into the development of adult light organs and flash signal control in fireflies.
    DOI:  https://doi.org/10.1038/s41467-024-45559-7
  20. Nat Med. 2024 Mar 08.
    Sex-specific genetic architecture of blood pressure.
    Min-Lee Yang, Chang Xu, Trisha Gupte, Thomas J Hoffmann, Carlos Iribarren, Xiang Zhou, Santhi K Ganesh.
      The genetic and genomic basis of sex differences in blood pressure (BP) traits remain unstudied at scale. Here, we conducted sex-stratified and combined-sex genome-wide association studies of BP traits using the UK Biobank resource, identifying 1,346 previously reported and 29 new BP trait-associated loci. Among associated loci, 412 were female-specific (Pfemale ≤ 5 × 10-8; Pmale > 5 × 10-8) and 142 were male-specific (Pmale ≤ 5 × 10-8; Pfemale > 5 × 10-8); these sex-specific loci were enriched for hormone-related transcription factors, in particular, estrogen receptor 1. Analyses of gene-by-sex interactions and sexually dimorphic effects identified four genomic regions, showing female-specific associations with diastolic BP or pulse pressure, including the chromosome 13q34-COL4A1/COL4A2 locus. Notably, female-specific pulse pressure-associated loci exhibited enriched acetylated histone H3 Lys27 modifications in arterial tissues and a female-specific association with fibromuscular dysplasia, a female-biased vascular disease; colocalization signals included Chr13q34: COL4A1/COL4A2, Chr9p21: CDKN2B-AS1 and Chr4q32.1: MAP9 regions. Sex-specific and sex-biased polygenic associations of BP traits were associated with multiple cardiovascular traits. These findings suggest potentially clinically significant and BP sex-specific pleiotropic effects on cardiovascular diseases.
    DOI:  https://doi.org/10.1038/s41591-024-02858-2
  21. J Exp Med. 2024 Apr 01. pii: e20231282. [Epub ahead of print]221(4):
    Site-specific regulation of Th2 differentiation within lymph node microenvironments.
    Miranda R Lyons-Cohen, Elya A Shamskhou, Michael Y Gerner.
      T helper 2 (Th2) responses protect against pathogens while also driving allergic inflammation, yet how large-scale Th2 responses are generated in tissue context remains unclear. Here, we used quantitative imaging to investigate early Th2 differentiation within lymph nodes (LNs) following cutaneous allergen administration. Contrary to current models, we observed extensive activation and "macro-clustering" of early Th2 cells with migratory type-2 dendritic cells (cDC2s), generating specialized Th2-promoting microenvironments. Macro-clustering was integrin-mediated and promoted localized cytokine exchange among T cells to reinforce differentiation, which contrasted the behavior during Th1 responses. Unexpectedly, formation of Th2 macro-clusters was dependent on the site of skin sensitization. Differences between sites were driven by divergent activation states of migratory cDC2 from different dermal tissues, with enhanced costimulatory molecule expression by cDC2 in Th2-generating LNs promoting prolonged T cell activation, macro-clustering, and cytokine sensing. Thus, the generation of dedicated Th2 priming microenvironments through enhanced costimulatory molecule signaling initiates Th2 responses in vivo and occurs in a skin site-specific manner.
    DOI:  https://doi.org/10.1084/jem.20231282
  22. Nature. 2024 Mar 06.
    Interactions between immune cells recorded.
    Michael A Wheeler.
      
    Keywords:  Cell biology; Immunology
    DOI:  https://doi.org/10.1038/d41586-024-00426-9
  23. Nat Commun. 2024 Mar 04. 15(1): 1955
    A humanized mouse model for adeno-associated viral gene therapy.
    Mercedes Barzi, Tong Chen, Trevor J Gonzalez, Francis P Pankowicz, Seh Hoon Oh, Helen L Streff, Alan Rosales, Yunhan Ma, Sabrina Collias, Sarah E Woodfield, Anna Mae Diehl, Sanjeev A Vasudevan, Thao N Galvan, John Goss, Charles A Gersbach, Beatrice Bissig-Choisat, Aravind Asokan, Karl-Dimiter Bissig.
      Clinical translation of AAV-mediated gene therapy requires preclinical development across different experimental models, often confounded by variable transduction efficiency. Here, we describe a human liver chimeric transgene-free Il2rg-/-/Rag2-/-/Fah-/-/Aavr-/- (TIRFA) mouse model overcoming this translational roadblock, by combining liver humanization with AAV receptor (AAVR) ablation, rendering murine cells impermissive to AAV transduction. Using human liver chimeric TIRFA mice, we demonstrate increased transduction of clinically used AAV serotypes in primary human hepatocytes compared to humanized mice with wild-type AAVR. Further, we demonstrate AAV transduction in human teratoma-derived primary cells and liver cancer tissue, displaying the versatility of the humanized TIRFA mouse. From a mechanistic perspective, our results support the notion that AAVR functions as both an entry receptor and an intracellular receptor essential for transduction. The TIRFA mouse should allow prediction of AAV gene transfer efficiency and the study of AAV vector biology in a preclinical human setting.
    DOI:  https://doi.org/10.1038/s41467-024-46017-0
  24. Sci Immunol. 2024 Mar 08. 9(93): eade6256
    Transmembrane domain-driven PD-1 dimers mediate T cell inhibition.
    Elliot A Philips, Jia Liu, Audun Kvalvaag, Alexander M Mørch, Anna S Tocheva, Charles Ng, Hong Liang, Ian M Ahearn, Ruimin Pan, Christina C Luo, Alexander Leithner, Zhihua Qin, Yong Zhou, Antonio Garcia-España, Adam Mor, Dan R Littman, Michael L Dustin, Jun Wang, Xiang-Peng Kong.
      Programmed cell death-1 (PD-1) is a potent immune checkpoint receptor on T lymphocytes. Upon engagement by its ligands, PD-L1 or PD-L2, PD-1 inhibits T cell activation and can promote immune tolerance. Antagonism of PD-1 signaling has proven effective in cancer immunotherapy, and conversely, agonists of the receptor may have a role in treating autoimmune disease. Some immune receptors function as dimers, but PD-1 has been considered monomeric. Here, we show that PD-1 and its ligands form dimers as a consequence of transmembrane domain interactions and that propensity for dimerization correlates with the ability of PD-1 to inhibit immune responses, antitumor immunity, cytotoxic T cell function, and autoimmune tissue destruction. These observations contribute to our understanding of the PD-1 axis and how it can potentially be manipulated for improved treatment of cancer and autoimmune diseases.
    DOI:  https://doi.org/10.1126/sciimmunol.ade6256
  25. Cell Metab. 2024 Mar 05. pii: S1550-4131(24)00049-4. [Epub ahead of print]36(3): 461-462
    Carnosine facilitates lysosomal release of inhibitors of T cell surveillance.
    Pawel Swietach, Marja Jäättelä, Shari Pillon-Thomas, Ebbe Boedtkjer.
      Cancer metabolism produces large fluxes of lactate and H+, which are extruded by membrane transporters. However, H+ production and extrusion must be coupled by diffusion, facilitated by mobile buffers. Yan et al. propose that carnosine, generated by CARNS2, provides this mobile buffering and enables lysosomal functions that block T cell surveillance.
    DOI:  https://doi.org/10.1016/j.cmet.2024.02.003
  26. Nat Commun. 2024 Mar 04. 15(1): 1982
    Inactivation of cytidine triphosphate synthase 1 prevents fatal auto-immunity in mice.
    Claire Soudais, Romane Schaus, Camille Bachelet, Norbert Minet, Sara Mouasni, Cécile Garcin, Caique Lopes Souza, Pierre David, Clara Cousu, Hélène Asnagli, Andrew Parker, Paul Palmquist-Gomes, Fernando E Sepulveda, Sébastien Storck, Sigolène M Meilhac, Alain Fischer, Emmanuel Martin, Sylvain Latour.
      De novo synthesis of the pyrimidine, cytidine triphosphate (CTP), is crucial for DNA/RNA metabolism and depends on the CTP synthetases, CTPS1 and -2. Partial CTPS1 deficiency in humans has previously been shown to lead to immunodeficiency, with impaired expansion of T and B cells. Here, we examine the effects of conditional and inducible inactivation of Ctps1 and/or Ctps2 on mouse embryonic development and immunity. We report that deletion of Ctps1, but not Ctps2, is embryonic-lethal. Tissue and cells with high proliferation and renewal rates, such as intestinal epithelium, erythroid and thymic lineages, activated B and T lymphocytes, and memory T cells strongly rely on CTPS1 for their maintenance and growth. However, both CTPS1 and CTPS2 are required for T cell proliferation following TCR stimulation. Deletion of Ctps1 in T cells or treatment with a CTPS1 inhibitor rescued Foxp3-deficient mice from fatal systemic autoimmunity and reduced the severity of experimental autoimmune encephalomyelitis. These findings support that CTPS1 may represent a target for immune suppression.
    DOI:  https://doi.org/10.1038/s41467-024-45805-y
  27. Nat Cell Biol. 2024 Mar 07.
    WIPI4 loss linked to ferroptosis.
    Yang Liu, Hongyuan Yang.
      
    DOI:  https://doi.org/10.1038/s41556-024-01359-1
  28. Proc Natl Acad Sci U S A. 2024 Mar 12. 121(11): e2317658121
    Sustained AhR activity programs memory fate of early effector CD8+ T cells.
    Huafeng Zhang, Zhuoshun Yang, Wu Yuan, Jincheng Liu, Xiao Luo, Qian Zhang, Yonggang Li, Jie Chen, Yabo Zhou, Jiadi Lv, Nannan Zhou, Jingwei Ma, Ke Tang, Bo Huang.
      Identification of mechanisms that program early effector T cells to either terminal effector T (Teff) or memory T (Tm) cells has important implications for protective immunity against infections and cancers. Here, we show that the cytosolic transcription factor aryl hydrocarbon receptor (AhR) is used by early Teff cells to program memory fate. Upon antigen engagement, AhR is rapidly up-regulated via reactive oxygen species signaling in early CD8+ Teff cells, which does not affect the effector response, but is required for memory formation. Mechanistically, activated CD8+ T cells up-regulate HIF-1α to compete with AhR for HIF-1β, leading to the loss of AhR activity in HIF-1αhigh short-lived effector cells, but sustained in HIF-1αlow memory precursor effector cells (MPECs) with the help of autocrine IL-2. AhR then licenses CD8+ MPECs in a quiescent state for memory formation. These findings partially resolve the long-standing issue of how Teff cells are regulated to differentiate into memory cells.
    Keywords:  CD8+ memory T cells; HIF-1α; aryl hydrocarbon receptor; transcription factor
    DOI:  https://doi.org/10.1073/pnas.2317658121
  29. Immunity. 2024 Mar 01. pii: S1074-7613(24)00081-5. [Epub ahead of print]
    Tuning of plasma cell lifespan by competition explains the longevity and heterogeneity of antibody persistence.
    Benjamin D Simons, Omer Karin.
      Plasma cells that emerge after infection or vaccination exhibit heterogeneous lifespans; most survive for days to months, whereas others persist for decades, providing antigen-specific long-term protection. We developed a mathematical framework to explore the dynamics of plasma cell removal and its regulation by survival factors. Analyses of antibody persistence following hepatitis A and B and HPV vaccination revealed specific patterns of longevity and heterogeneity within and between responses, implying that this process is fine-tuned near a critical "flat" state between two dynamic regimes. This critical state reflects the tuning of rates of the underlying regulatory network and is highly sensitive to variation in parameters, which amplifies lifespan differences between cells. We propose that fine-tuning is the generic outcome of competition over shared survival signals, with a competition-based mechanism providing a unifying explanation for a wide range of experimental observations, including the dynamics of plasma cell accumulation and the effects of survival factor deletion. Our theory is testable, and we provide specific predictions.
    Keywords:  antibody memory; collective dynamic; dynamical systems; immune memory; plasma cells; self-tuning; systems biology; systems immunology; tuning by competition; vaccines
    DOI:  https://doi.org/10.1016/j.immuni.2024.02.005
  30. Nat Commun. 2024 Mar 07. 15(1): 2085
    Chloride intracellular channel (CLIC) proteins function as fusogens.
    Bar Manori, Alisa Vaknin, Pavla Vaňková, Anat Nitzan, Ronen Zaidel-Bar, Petr Man, Moshe Giladi, Yoni Haitin.
      Chloride Intracellular Channel (CLIC) family members uniquely transition between soluble and membrane-associated conformations. Despite decades of extensive functional and structural studies, CLICs' function as ion channels remains debated, rendering our understanding of their physiological role incomplete. Here, we expose the function of CLIC5 as a fusogen. We demonstrate that purified CLIC5 directly interacts with the membrane and induces fusion, as reflected by increased liposomal diameter and lipid and content mixing between liposomes. Moreover, we show that this activity is facilitated by acidic pH, a known trigger for CLICs' transition to a membrane-associated conformation, and that increased exposure of the hydrophobic inter-domain interface is crucial for this process. Finally, mutation of a conserved hydrophobic interfacial residue diminishes the fusogenic activity of CLIC5 in vitro and impairs excretory canal extension in C. elegans in vivo. Together, our results unravel the long-sought physiological role of these enigmatic proteins.
    DOI:  https://doi.org/10.1038/s41467-024-46301-z
  31. Nat Neurosci. 2024 Mar;27(3): 390
    The eyes have it.
    Leonie Welberg.
      
    DOI:  https://doi.org/10.1038/s41593-024-01601-x
  32. Nat Commun. 2024 Mar 08. 15(1): 2113
    Spatially-resolved transcriptomics reveal macrophage heterogeneity and prognostic significance in diffuse large B-cell lymphoma.
    Min Liu, Giorgio Bertolazzi, Shruti Sridhar, Rui Xue Lee, Patrick Jaynes, Kevin Mulder, Nicholas Syn, Michal Marek Hoppe, Shuangyi Fan, Yanfen Peng, Jocelyn Thng, Reiya Chua, Jayalakshmi, Yogeshini Batumalai, Sanjay De Mel, Limei Poon, Esther Hian Li Chan, Joanne Lee, Susan Swee-Shan Hue, Sheng-Tsung Chang, Shih-Sung Chuang, K George Chandy, Xiaofei Ye, Qiang Pan-Hammarström, Florent Ginhoux, Yen Lin Chee, Siok-Bian Ng, Claudio Tripodo, Anand D Jeyasekharan.
      Macrophages are abundant immune cells in the microenvironment of diffuse large B-cell lymphoma (DLBCL). Macrophage estimation by immunohistochemistry shows varying prognostic significance across studies in DLBCL, and does not provide a comprehensive analysis of macrophage subtypes. Here, using digital spatial profiling with whole transcriptome analysis of CD68+ cells, we characterize macrophages in distinct spatial niches of reactive lymphoid tissues (RLTs) and DLBCL. We reveal transcriptomic differences between macrophages within RLTs (light zone /dark zone, germinal center/ interfollicular), and between disease states (RLTs/ DLBCL), which we then use to generate six spatially-derived macrophage signatures (MacroSigs). We proceed to interrogate these MacroSigs in macrophage and DLBCL single-cell RNA-sequencing datasets, and in gene-expression data from multiple DLBCL cohorts. We show that specific MacroSigs are associated with cell-of-origin subtypes and overall survival in DLBCL. This study provides a spatially-resolved whole-transcriptome atlas of macrophages in reactive and malignant lymphoid tissues, showing biological and clinical significance.
    DOI:  https://doi.org/10.1038/s41467-024-46220-z
  33. Nat Commun. 2024 Mar 06. 15(1): 2058
    BHLHE40/41 regulate microglia and peripheral macrophage responses associated with Alzheimer's disease and other disorders of lipid-rich tissues.
    Anna Podleśny-Drabiniok, Gloriia Novikova, Yiyuan Liu, Josefine Dunst, Rose Temizer, Chiara Giannarelli, Samuele Marro, Taras Kreslavsky, Edoardo Marcora, Alison Mary Goate.
      Genetic and experimental evidence suggests that Alzheimer's disease (AD) risk alleles and genes may influence disease susceptibility by altering the transcriptional and cellular responses of macrophages, including microglia, to damage of lipid-rich tissues like the brain. Recently, sc/nRNA sequencing studies identified similar transcriptional activation states in subpopulations of macrophages in aging and degenerating brains and in other diseased lipid-rich tissues. We collectively refer to these subpopulations of microglia and peripheral macrophages as DLAMs. Using macrophage sc/nRNA-seq data from healthy and diseased human and mouse lipid-rich tissues, we reconstructed gene regulatory networks and identified 11 strong candidate transcriptional regulators of the DLAM response across species. Loss or reduction of two of these transcription factors, BHLHE40/41, in iPSC-derived microglia and human THP-1 macrophages as well as loss of Bhlhe40/41 in mouse microglia, resulted in increased expression of DLAM genes involved in cholesterol clearance and lysosomal processing, increased cholesterol efflux and storage, and increased lysosomal mass and degradative capacity. These findings provide targets for therapeutic modulation of macrophage/microglial function in AD and other disorders affecting lipid-rich tissues.
    DOI:  https://doi.org/10.1038/s41467-024-46315-7
  34. Nat Cell Biol. 2024 Mar 07.
    Lipid droplets and cellular lipid flux.
    Alyssa J Mathiowetz, James A Olzmann.
      Lipid droplets are dynamic organelles that store neutral lipids, serve the metabolic needs of cells, and sequester lipids to prevent lipotoxicity and membrane damage. Here we review the current understanding of the mechanisms of lipid droplet biogenesis and turnover, the transfer of lipids and metabolites at membrane contact sites, and the role of lipid droplets in regulating fatty acid flux in lipotoxicity and cell death.
    DOI:  https://doi.org/10.1038/s41556-024-01364-4
  35. Nat Commun. 2024 Mar 08. 15(1): 2140
    Structural basis for self-discrimination by neoantigen-specific TCRs.
    John P Finnigan, Jenna H Newman, Yury Patskovsky, Larysa Patskovska, Andrew S Ishizuka, Geoffrey M Lynn, Robert A Seder, Michelle Krogsgaard, Nina Bhardwaj.
      T cell receptors (TCR) are pivotal in mediating tumour cell cytolysis via recognition of mutation-derived tumour neoantigens (neoAgs) presented by major histocompatibility class-I (MHC-I). Understanding the factors governing the emergence of neoAg from somatic mutations is a major focus of current research. However, the structural and cellular determinants controlling TCR recognition of neoAgs remain poorly understood. This study describes the multi-level analysis of a model neoAg from the B16F10 murine melanoma, H2-Db/Hsf2 p.K72N68-76, as well as its cognate TCR 47BE7. Through cellular, molecular and structural studies we demonstrate that the p.K72N mutation enhances H2-Db binding, thereby improving cell surface presentation and stabilizing the TCR 47BE7 epitope. Furthermore, TCR 47BE7 exhibited high functional avidity and selectivity, attributable to a broad, stringent, binding interface enabling recognition of native B16F10 despite low antigen density. Our findings provide insight into the generation of anchor-residue modified neoAg, and emphasize the value of molecular and structural investigations of neoAg in diverse MHC-I contexts for advancing the understanding of neoAg immunogenicity.
    DOI:  https://doi.org/10.1038/s41467-024-46367-9
  36. Nat Genet. 2024 Mar 07.
    MYC activity at enhancers drives prognostic transcriptional programs through an epigenetic switch.
    Simon T Jakobsen, Rikke A M Jensen, Maria S Madsen, Tina Ravnsborg, Christian S Vaagenso, Majken S Siersbæk, Hjorleifur Einarsson, Robin Andersson, Ole N Jensen, Rasmus Siersbæk.
      The transcription factor MYC is overexpressed in most cancers, where it drives multiple hallmarks of cancer progression. MYC is known to promote oncogenic transcription by binding to active promoters. In addition, MYC has also been shown to invade distal enhancers when expressed at oncogenic levels, but this enhancer binding has been proposed to have low gene-regulatory potential. Here, we demonstrate that MYC directly regulates enhancer activity to promote cancer type-specific gene programs predictive of poor patient prognosis. MYC induces transcription of enhancer RNA through recruitment of RNA polymerase II (RNAPII), rather than regulating RNAPII pause-release, as is the case at promoters. This process is mediated by MYC-induced H3K9 demethylation and acetylation by GCN5, leading to enhancer-specific BRD4 recruitment through its bromodomains, which facilitates RNAPII recruitment. We propose that MYC drives prognostic cancer type-specific gene programs through induction of an enhancer-specific epigenetic switch, which can be targeted by BET and GCN5 inhibitors.
    DOI:  https://doi.org/10.1038/s41588-024-01676-z
  37. Nat Commun. 2024 Mar 07. 15(1): 2102
    Hypothalamic astrocyte NAD+ salvage pathway mediates the coupling of dietary fat overconsumption in a mouse model of obesity.
    Jae Woo Park, Se Eun Park, Wuhyun Koh, Won Hee Jang, Jong Han Choi, Eun Roh, Gil Myoung Kang, Seong Jun Kim, Hyo Sun Lim, Chae Beom Park, So Yeon Jeong, Sang Yun Moon, Chan Hee Lee, Sang Yeob Kim, Hyung Jin Choi, Se Hee Min, C Justin Lee, Min-Seon Kim.
      Nicotinamide adenine dinucleotide (NAD)+ serves as a crucial coenzyme in numerous essential biological reactions, and its cellular availability relies on the activity of the nicotinamide phosphoribosyltransferase (NAMPT)-catalyzed salvage pathway. Here we show that treatment with saturated fatty acids activates the NAD+ salvage pathway in hypothalamic astrocytes. Furthermore, inhibition of this pathway mitigates hypothalamic inflammation and attenuates the development of obesity in male mice fed a high-fat diet (HFD). Mechanistically, CD38 functions downstream of the NAD+ salvage pathway in hypothalamic astrocytes burdened with excess fat. The activation of the astrocytic NAMPT-NAD+-CD38 axis in response to fat overload induces proinflammatory responses in the hypothalamus. It also leads to aberrantly activated basal Ca2+ signals and compromised Ca2+ responses to metabolic hormones such as insulin, leptin, and glucagon-like peptide 1, ultimately resulting in dysfunctional hypothalamic astrocytes. Our findings highlight the significant contribution of the hypothalamic astrocytic NAD+ salvage pathway, along with its downstream CD38, to HFD-induced obesity.
    DOI:  https://doi.org/10.1038/s41467-024-46009-0
  38. J Exp Med. 2024 Apr 01. pii: e20232000. [Epub ahead of print]221(4):
    Cholesterol 25-hydroxylase mediates neuroinflammation and neurodegeneration in a mouse model of tauopathy.
    Danira Toral-Rios, Justin M Long, Jason D Ulrich, Jinsheng Yu, Michael R Strickland, Xianlin Han, David M Holtzman, Anil G Cashikar, Steven M Paul.
      Alzheimer's disease (AD) is characterized by amyloid plaques and neurofibrillary tangles, in addition to neuroinflammation and changes in brain lipid metabolism. 25-Hydroxycholesterol (25-HC), a known modulator of both inflammation and lipid metabolism, is produced by cholesterol 25-hydroxylase encoded by Ch25h expressed as a "disease-associated microglia" signature gene. However, whether Ch25h influences tau-mediated neuroinflammation and neurodegeneration is unknown. Here, we show that in the absence of Ch25h and the resultant reduction in 25-HC, there is strikingly reduced age-dependent neurodegeneration and neuroinflammation in the hippocampus and entorhinal/piriform cortex of PS19 mice, which express the P301S mutant human tau transgene. Transcriptomic analyses of bulk hippocampal tissue and single nuclei revealed that Ch25h deficiency in PS19 mice strongly suppressed proinflammatory signaling in microglia. Our results suggest a key role for Ch25h/25-HC in potentiating proinflammatory signaling to promote tau-mediated neurodegeneration. Ch25h may represent a novel therapeutic target for primary tauopathies, AD, and other neuroinflammatory diseases.
    DOI:  https://doi.org/10.1084/jem.20232000
  39. Nat Commun. 2024 Mar 07. 15(1): 2095
    Pla2g12b drives expansion of triglyceride-rich lipoproteins.
    James H Thierer, Ombretta Foresti, Pradeep Kumar Yadav, Meredith H Wilson, Tabea O C Moll, Meng-Chieh Shen, Elisabeth M Busch-Nentwich, Margaret Morash, Karen L Mohlke, John F Rawls, Vivek Malhotra, M Mahmood Hussain, Steven A Farber.
      Vertebrates transport hydrophobic triglycerides through the circulatory system by packaging them within amphipathic particles called Triglyceride-Rich Lipoproteins. Yet, it remains largely unknown how triglycerides are loaded onto these particles. Mutations in Phospholipase A2 group 12B (PLA2G12B) are known to disrupt lipoprotein homeostasis, but its mechanistic role in this process remains unclear. Here we report that PLA2G12B channels lipids within the lumen of the endoplasmic reticulum into nascent lipoproteins. This activity promotes efficient lipid secretion while preventing excess accumulation of intracellular lipids. We characterize the functional domains, subcellular localization, and interacting partners of PLA2G12B, demonstrating that PLA2G12B is calcium-dependent and tightly associated with the membrane of the endoplasmic reticulum. We also detect profound resistance to atherosclerosis in PLA2G12B mutant mice, suggesting an evolutionary tradeoff between triglyceride transport and cardiovascular disease risk. Here we identify PLA2G12B as a key driver of triglyceride incorporation into vertebrate lipoproteins.
    DOI:  https://doi.org/10.1038/s41467-024-46102-4
  40. Nat Commun. 2024 Mar 05. 15(1): 1995
    ALKBH5-mediated m6A modification of IL-11 drives macrophage-to-myofibroblast transition and pathological cardiac fibrosis in mice.
    Tao Zhuang, Mei-Hua Chen, Ruo-Xi Wu, Jing Wang, Xi-De Hu, Ting Meng, Ai-Hua Wu, Yan Li, Yong-Feng Yang, Yu Lei, Dong-Hua Hu, Yan-Xiu Li, Li Zhang, Ai-Jun Sun, Wei Lu, Guan-Nan Zhang, Jun-Li Zuo, Cheng-Chao Ruan.
      Cardiac macrophage contributes to the development of cardiac fibrosis, but factors that regulate cardiac macrophages transition and activation during this process remains elusive. Here we show, by single-cell transcriptomics, lineage tracing and parabiosis, that cardiac macrophages from circulating monocytes preferentially commit to macrophage-to-myofibroblast transition (MMT) under angiotensin II (Ang II)-induced hypertension, with accompanying increased expression of the RNA N6-methyladenosine demethylases, ALKBH5. Meanwhile, macrophage-specific knockout of ALKBH5 inhibits Ang II-induced MMT, and subsequently ameliorates cardiac fibrosis and dysfunction. Mechanistically, RNA immunoprecipitation sequencing identifies interlukin-11 (IL-11) mRNA as a target for ALKBH5-mediated m6A demethylation, leading to increased IL-11 mRNA stability and protein levels. By contrast, overexpression of IL11 in circulating macrophages reverses the phenotype in ALKBH5-deficient mice and macrophage. Lastly, targeted delivery of ALKBH5 or IL-11 receptor α (IL11RA1) siRNA to monocytes/macrophages attenuates MMT and cardiac fibrosis under hypertensive stress. Our results thus suggest that the ALKBH5/IL-11/IL11RA1/MMT axis alters cardiac macrophage and contributes to hypertensive cardiac fibrosis and dysfunction in mice, and thereby identify potential targets for cardiac fibrosis therapy in patients.
    DOI:  https://doi.org/10.1038/s41467-024-46357-x
  41. Nat Commun. 2024 Mar 07. 15(1): 1528
    RHBDL4-triggered downregulation of COPII adaptor protein TMED7 suppresses TLR4-mediated inflammatory signaling.
    Julia D Knopf, Susanne S Steigleder, Friederike Korn, Nathalie Kühnle, Marina Badenes, Marina Tauber, Sebastian J Theobald, Jan Rybniker, Colin Adrain, Marius K Lemberg.
      The toll-like receptor 4 (TLR4) is a central regulator of innate immunity that primarily recognizes bacterial lipopolysaccharide cell wall constituents to trigger cytokine secretion. We identify the intramembrane protease RHBDL4 as a negative regulator of TLR4 signaling. We show that RHBDL4 triggers degradation of TLR4's trafficking factor TMED7. This counteracts TLR4 transport to the cell surface. Notably, TLR4 activation mediates transcriptional upregulation of RHBDL4 thereby inducing a negative feedback loop to reduce TLR4 trafficking to the plasma membrane. This secretory cargo tuning mechanism prevents the over-activation of TLR4-dependent signaling in an in vitro Mycobacterium tuberculosis macrophage infection model and consequently alleviates septic shock in a mouse model. A hypomorphic RHBDL4 mutation linked to Kawasaki syndrome, an ill-defined inflammatory disorder in children, further supports the pathophysiological relevance of our findings. In this work, we identify an RHBDL4-mediated axis that acts as a rheostat to prevent over-activation of the TLR4 pathway.
    DOI:  https://doi.org/10.1038/s41467-024-45615-2
  42. Commun Biol. 2024 Mar 07. 7(1): 283
    SAM68 directs STING signaling to apoptosis in macrophages.
    Demi van der Horst, Naziia Kurmasheva, Mikkel H S Marqvorsen, Sonia Assil, Anna H F Rahimic, Christoph F Kollmann, Leandro Silva da Costa, Qi Wu, Jian Zhao, Eleonora Cesari, Marie B Iversen, Fanghui Ren, Trine I Jensen, Ryo Narita, Vivien R Schack, Bao-Cun Zhang, Rasmus O Bak, Claudio Sette, Robert A Fenton, Jacob G Mikkelsen, Søren R Paludan, David Olagnier.
      DNA is a danger signal sensed by cGAS to engage signaling through STING to activate innate immune functions. The best-studied downstream responses to STING activation include expression of type I interferon and inflammatory genes, but STING also activates other pathways, including apoptosis. Here, we report that STING-dependent induction of apoptosis in macrophages occurs through the intrinsic mitochondrial pathway and is mediated via IRF3 but acts independently of gene transcription. By intersecting four mass spectrometry datasets, we identify SAM68 as crucial for the induction of apoptosis downstream of STING activation. SAM68 is essential for the full activation of apoptosis. Still, it is not required for STING-mediated activation of IFN expression or activation of NF-κB. Mechanistic studies reveal that protein trafficking is required and involves SAM68 recruitment to STING upon activation, with the two proteins associating at the Golgi or a post-Golgi compartment. Collectively, our work identifies SAM68 as a STING-interacting protein enabling induction of apoptosis through this DNA-activated innate immune pathway.
    DOI:  https://doi.org/10.1038/s42003-024-05969-1
  43. Nature. 2024 Mar 06.
    Genome-wide characterization of circulating metabolic biomarkers.
    China Kadoorie Biobank Collaborative Group
      Genome-wide association analyses using high-throughput metabolomics platforms have led to novel insights into the biology of human metabolism1-7. This detailed knowledge of the genetic determinants of systemic metabolism has been pivotal for uncovering how genetic pathways influence biological mechanisms and complex diseases8-11. Here we present a genome-wide association study for 233 circulating metabolic traits quantified by nuclear magnetic resonance spectroscopy in up to 136,016 participants from 33 cohorts. We identify more than 400 independent loci and assign probable causal genes at two-thirds of these using manual curation of plausible biological candidates. We highlight the importance of sample and participant characteristics that can have significant effects on genetic associations. We use detailed metabolic profiling of lipoprotein- and lipid-associated variants to better characterize how known lipid loci and novel loci affect lipoprotein metabolism at a granular level. We demonstrate the translational utility of comprehensively phenotyped molecular data, characterizing the metabolic associations of intrahepatic cholestasis of pregnancy. Finally, we observe substantial genetic pleiotropy for multiple metabolic pathways and illustrate the importance of careful instrument selection in Mendelian randomization analysis, revealing a putative causal relationship between acetone and hypertension. Our publicly available results provide a foundational resource for the community to examine the role of metabolism across diverse diseases.
    DOI:  https://doi.org/10.1038/s41586-024-07148-y
  44. Science. 2024 Mar 08. 383(6687): 1122-1130
    Sister chromatid cohesion is mediated by individual cohesin complexes.
    Fena Ochs, Charlotte Green, Aleksander Tomasz Szczurek, Lior Pytowski, Sofia Kolesnikova, Jill Brown, Daniel Wolfram Gerlich, Veronica Buckle, Lothar Schermelleh, Kim Ashley Nasmyth.
      Eukaryotic genomes are organized by loop extrusion and sister chromatid cohesion, both mediated by the multimeric cohesin protein complex. Understanding how cohesin holds sister DNAs together, and how loss of cohesion causes age-related infertility in females, requires knowledge as to cohesin's stoichiometry in vivo. Using quantitative super-resolution imaging, we identified two discrete populations of chromatin-bound cohesin in postreplicative human cells. Whereas most complexes appear dimeric, cohesin that localized to sites of sister chromatid cohesion and associated with sororin was exclusively monomeric. The monomeric stoichiometry of sororin:cohesin complexes demonstrates that sister chromatid cohesion is conferred by individual cohesin rings, a key prediction of the proposal that cohesion arises from the co-entrapment of sister DNAs.
    DOI:  https://doi.org/10.1126/science.adl4606
  45. Nat Biomed Eng. 2024 Mar 04.
    Severely polarized extracellular acidity around tumour cells.
    Qiang Feng, Zachary Bennett, Anthony Grichuk, Raymundo Pantoja, Tongyi Huang, Brandon Faubert, Gang Huang, Mingyi Chen, Ralph J DeBerardinis, Baran D Sumer, Jinming Gao.
      Extracellular pH impacts many molecular, cellular and physiological processes, and hence is tightly regulated. Yet, in tumours, dysregulated cancer cell metabolism and poor vascular perfusion cause the tumour microenvironment to become acidic. Here by leveraging fluorescent pH nanoprobes with a transistor-like activation profile at a pH of 5.3, we show that, in cancer cells, hydronium ions are excreted into a small extracellular region. Such severely polarized acidity (pH <5.3) is primarily caused by the directional co-export of protons and lactate, as we show for a diverse panel of cancer cell types via the genetic knockout or inhibition of monocarboxylate transporters, and also via nanoprobe activation in multiple tumour models in mice. We also observed that such spot acidification in ex vivo stained snap-frozen human squamous cell carcinoma tissue correlated with the expression of monocarboxylate transporters and with the exclusion of cytotoxic T cells. Severely spatially polarized tumour acidity could be leveraged for cancer diagnosis and therapy.
    DOI:  https://doi.org/10.1038/s41551-024-01178-7
  46. Nature. 2024 Mar;627(8003): 266
    Roger Guillemin (1924-2024), neuroscientist who showed how the brain controls hormones.
    Greg Lemke.
      
    Keywords:  Medical research; Metabolism; Neuroscience
    DOI:  https://doi.org/10.1038/d41586-024-00714-4
  47. Cell Metab. 2024 Feb 27. pii: S1550-4131(24)00056-1. [Epub ahead of print]
    Age-related ciliopathy: Obesogenic shortening of melanocortin-4 receptor-bearing neuronal primary cilia.
    Manami Oya, Yoshiki Miyasaka, Yoshiko Nakamura, Miyako Tanaka, Takayoshi Suganami, Tomoji Mashimo, Kazuhiro Nakamura.
      Obesity is often associated with aging. However, the mechanism of age-related obesity is unknown. The melanocortin-4 receptor (MC4R) mediates leptin-melanocortin anti-obesity signaling in the hypothalamus. Here, we discovered that MC4R-bearing primary cilia of hypothalamic neurons progressively shorten with age in rats, correlating with age-dependent metabolic decline and increased adiposity. This "age-related ciliopathy" is promoted by overnutrition-induced upregulation of leptin-melanocortin signaling and inhibited or reversed by dietary restriction or the knockdown of ciliogenesis-associated kinase 1 (CILK1). Forced shortening of MC4R-bearing cilia in hypothalamic neurons by genetic approaches impaired neuronal sensitivity to melanocortin and resulted in decreased brown fat thermogenesis and energy expenditure and increased appetite, finally developing obesity and leptin resistance. Therefore, despite its acute anti-obesity effect, chronic leptin-melanocortin signaling increases susceptibility to obesity by promoting the age-related shortening of MC4R-bearing cilia. This study provides a crucial mechanism for age-related obesity, which increases the risk of metabolic syndrome.
    Keywords:  aging; brown adipose tissue; cilia; dorsomedial hypothalamus; intraflagellar transport; leptin; melanocortin; obesity; paraventricular hypothalamic nucleus; thermoregulation
    DOI:  https://doi.org/10.1016/j.cmet.2024.02.010
  48. Nat Commun. 2024 Mar 04. 15(1): 1962
    Genetic architecture of the structural connectome.
    Michael Wainberg, Natalie J Forde, Salim Mansour, Isabel Kerrebijn, Sarah E Medland, Colin Hawco, Shreejoy J Tripathy.
      Myelinated axons form long-range connections that enable rapid communication between distant brain regions, but how genetics governs the strength and organization of these connections remains unclear. We perform genome-wide association studies of 206 structural connectivity measures derived from diffusion magnetic resonance imaging tractography of 26,333 UK Biobank participants, each representing the density of myelinated connections within or between a pair of cortical networks, subcortical structures or cortical hemispheres. We identify 30 independent genome-wide significant variants after Bonferroni correction for the number of measures studied (126 variants at nominal genome-wide significance) implicating genes involved in myelination (SEMA3A), neurite elongation and guidance (NUAK1, STRN, DPYSL2, EPHA3, SEMA3A, HGF, SHTN1), neural cell proliferation and differentiation (GMNC, CELF4, HGF), neuronal migration (CCDC88C), cytoskeletal organization (CTTNBP2, MAPT, DAAM1, MYO16, PLEC), and brain metal transport (SLC39A8). These variants have four broad patterns of spatial association with structural connectivity: some have disproportionately strong associations with corticothalamic connectivity, interhemispheric connectivity, or both, while others are more spatially diffuse. Structural connectivity measures are highly polygenic, with a median of 9.1 percent of common variants estimated to have non-zero effects on each measure, and exhibited signatures of negative selection. Structural connectivity measures have significant genetic correlations with a variety of neuropsychiatric and cognitive traits, indicating that connectivity-altering variants tend to influence brain health and cognitive function. Heritability is enriched in regions with increased chromatin accessibility in adult oligodendrocytes (as well as microglia, inhibitory neurons and astrocytes) and multiple fetal cell types, suggesting that genetic control of structural connectivity is partially mediated by effects on myelination and early brain development. Our results indicate pervasive, pleiotropic, and spatially structured genetic control of white-matter structural connectivity via diverse neurodevelopmental pathways, and support the relevance of this genetic control to healthy brain function.
    DOI:  https://doi.org/10.1038/s41467-024-46023-2
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