bims-nimamd Biomed News
on Neuroimmunity and neuroinflammation in ageing and metabolic disease
Issue of 2022–09–11
37 papers selected by
Fawaz Alzaïd, Sorbonne Université
  1. Multimodal single cell sequencing implicates chromatin accessibility and genetic background in diabetic kidney disease progression.
  2. The IFN-γ receptor promotes immune dysregulation and disease in STING gain-of-function mice.
  3. Adipocyte-derived lactate is a signalling metabolite that potentiates adipose macrophage inflammation via targeting PHD2.
  4. A RORγt+ cell instructs gut microbiota-specific Treg cell differentiation.
  5. Structure-function analysis of enterovirus protease 2A in complex with its essential host factor SETD3.
  6. In vivo tumor immune microenvironment phenotypes correlate with inflammation and vasculature to predict immunotherapy response.
  7. Induction of a colitogenic phenotype in Th1-like cells depends on interleukin-23 receptor signaling.
  8. Lactate increases stemness of CD8 + T cells to augment anti-tumor immunity.
  9. A bead-based method for high-throughput mapping of the sequence- and force-dependence of T cell activation.
  10. Beiging of perivascular adipose tissue regulates its inflammation and vascular remodeling.
  11. Novel antigen presenting cell imparts Treg-dependent tolerance to gut microbiota.
  12. Bidirectional lysosome transport: a balancing act between ARL8 effectors.
  13. 3D chromatin maps of the human pancreas reveal lineage-specific regulatory architecture of T2D risk.
  14. Dectin-1 signaling in neutrophils up-regulates PD-L1 and triggers ROS-mediated suppression of CD4+ T cells.
  15. Molecular basis for polysaccharide recognition and modulated ATP hydrolysis by the O antigen ABC transporter.
  16. Walking the high wire: How neurons maintain stability in the crossline of neurodegeneration.
  17. Antipsychotic drugs induce vascular defects in hematopoietic organs.
  18. The human disease gene LYSET is essential for lysosomal enzyme transport and viral infection.
  19. How cholesterol encourages a cell to bulk up.
  20. Spermidine-mediated hypusination of translation factor EIF5A improves mitochondrial fatty acid oxidation and prevents non-alcoholic steatohepatitis progression.
  21. Potential solutions for manufacture of CAR T cells in cancer immunotherapy.
  22. Clonal dynamics underlying the skewed CD4/CD8 ratio of mouse thymocytes revealed by TCR-independent barcoding.
  23. Regulation associated modules reflect 3D genome modularity associated with chromatin activity.
  24. Taz protects hematopoietic stem cells from an aging-dependent decrease in PU.1 activity.
  25. CAR-T cell therapy-related cytokine release syndrome and therapeutic response is modulated by the gut microbiome in hematologic malignancies.
  26. Gut-Brain Circuits for Fat Preference.
  27. Mitochondrial protein synthesis and the bioenergetic cost of neurodevelopment.
  28. Extracellular vesicles mediate the communication of adipose tissue with brain and promote cognitive impairment associated with insulin resistance.
  29. Pathological MAPK activation-mediated lymphatic basement membrane disruption causes lymphangiectasia that is treatable with ravoxertinib.
  30. Biomarker correlates with response to NY-ESO-1 TCR T cells in patients with synovial sarcoma.
  31. Did this gene give modern human brains their edge?
  32. The nucleolus is the site for inflammatory RNA decay during infection.
  33. A neurogenetic mechanism of experience-dependent suppression of aggression.
  34. Pronounced sequence specificity of the TET enzyme catalytic domain guides its cellular function.
  35. Allosteric inhibition of HTRA1 activity by a conformational lock mechanism to treat age-related macular degeneration.
  36. Genetic- and diet-induced ω-3 fatty acid enrichment enhances TRPV4-mediated vasodilation in mice.
  37. Brainstem ADCYAP1+ neurons control multiple aspects of sickness behaviour.
  1. Nat Commun. 2022 Sep 06. 13(1): 5253
    Multimodal single cell sequencing implicates chromatin accessibility and genetic background in diabetic kidney disease progression.
    Parker C Wilson, Yoshiharu Muto, Haojia Wu, Anil Karihaloo, Sushrut S Waikar, Benjamin D Humphreys.
      The proximal tubule is a key regulator of kidney function and glucose metabolism. Diabetic kidney disease leads to proximal tubule injury and changes in chromatin accessibility that modify the activity of transcription factors involved in glucose metabolism and inflammation. Here we use single nucleus RNA and ATAC sequencing to show that diabetic kidney disease leads to reduced accessibility of glucocorticoid receptor binding sites and an injury-associated expression signature in the proximal tubule. We hypothesize that chromatin accessibility is regulated by genetic background and closely-intertwined with metabolic memory, which pre-programs the proximal tubule to respond differently to external stimuli. Glucocorticoid excess has long been known to increase risk for type 2 diabetes, which raises the possibility that glucocorticoid receptor inhibition may mitigate the adverse metabolic effects of diabetic kidney disease.
    DOI:  https://doi.org/10.1038/s41467-022-32972-z
  2. JCI Insight. 2022 Sep 08. pii: e155250. [Epub ahead of print]7(17):
    The IFN-γ receptor promotes immune dysregulation and disease in STING gain-of-function mice.
    W Alexander Stinson, Cathrine A Miner, Fang R Zhao, Annena Jane Lundgren, Subhajit Poddar, Jonathan J Miner.
      STING gain-of-function mutations cause STING-associated vasculopathy with onset in infancy (SAVI) in humans, a disease characterized by spontaneous lung inflammation and fibrosis. Mice with STING gain-of-function mutations (SAVI mice) develop αβ T cell-dependent lung disease and also lack lymph nodes. Although SAVI has been regarded as a type I interferonopathy, the relative contributions of the three interferon receptors are incompletely understood. Here, we show that STING gain of function led to upregulation of IFN-γ-induced chemokines in the lungs of SAVI mice and that deletion of the type II IFN receptor (IFNGR1), but not the type I IFN receptor (IFNAR1) or type III IFN receptor (IFNλR1), ameliorated lung disease and restored lymph node development in SAVI mice. Furthermore, deletion of IFNGR1, but not IFNAR1 or IFNλR1, corrected the ratio of effector to Tregs in SAVI mice and in mixed bone marrow chimeric mice. Finally, cultured SAVI mouse macrophages were hyperresponsive to IFN-γ, but not IFN-β, in terms of Cxcl9 upregulation and cell activation. These results demonstrate that IFNGR1 plays a major role in autoinflammation and immune dysregulation mediated by STING gain of function.
    Keywords:  Autoimmune diseases; Autoimmunity; Inflammation; Innate immunity; Monogenic diseases
    DOI:  https://doi.org/10.1172/jci.insight.155250
  3. Nat Commun. 2022 Sep 05. 13(1): 5208
    Adipocyte-derived lactate is a signalling metabolite that potentiates adipose macrophage inflammation via targeting PHD2.
    Tianshi Feng, Xuemei Zhao, Ping Gu, Wah Yang, Cunchuan Wang, Qingyu Guo, Qiaoyun Long, Qing Liu, Ying Cheng, Jin Li, Cynthia Kwan Yui Cheung, Donghai Wu, Xinyu Kong, Yong Xu, Dewei Ye, Shuang Hua, Kerry Loomes, Aimin Xu, Xiaoyan Hui.
      Adipose tissue macrophage (ATM) inflammation is involved with meta-inflammation and pathology of metabolic complications. Here we report that in adipocytes, elevated lactate production, previously regarded as the waste product of glycolysis, serves as a danger signal to promote ATM polarization to an inflammatory state in the context of obesity. Adipocyte-selective deletion of lactate dehydrogenase A (Ldha), the enzyme converting pyruvate to lactate, protects mice from obesity-associated glucose intolerance and insulin resistance, accompanied by a lower percentage of inflammatory ATM and reduced production of pro-inflammatory cytokines such as interleukin 1β (IL-1β). Mechanistically, lactate, at its physiological concentration, fosters the activation of inflammatory macrophages by directly binding to the catalytic domain of prolyl hydroxylase domain-containing 2 (PHD2) in a competitive manner with α-ketoglutarate and stabilizes hypoxia inducible factor (HIF-1α). Lactate-induced IL-1β was abolished in PHD2-deficient macrophages. Human adipose lactate level is positively linked with local inflammatory features and insulin resistance index independent of the body mass index (BMI). Our study shows a critical function of adipocyte-derived lactate in promoting the pro-inflammatory microenvironment in adipose and identifies PHD2 as a direct sensor of lactate, which functions to connect chronic inflammation and energy metabolism.
    DOI:  https://doi.org/10.1038/s41467-022-32871-3
  4. Nature. 2022 Sep 07.
    A RORγt+ cell instructs gut microbiota-specific Treg cell differentiation.
    Ranit Kedmi, Tariq A Najar, Kailin R Mesa, Allyssa Grayson, Lina Kroehling, Yuhan Hao, Stephanie Hao, Maria Pokrovskii, Mo Xu, Jhimmy Talbot, Jiaxi Wang, Joe Germino, Caleb A Lareau, Ansuman T Satpathy, Mark S Anderson, Terri M Laufer, Iannis Aifantis, Juliet M Bartleson, Paul M Allen, Helena Paidassi, James M Gardner, Marlon Stoeckius, Dan R Littman.
      The mutualistic relationship of gut-resident microbiota and the host immune system promotes homeostasis that ensures maintenance of the microbial community and of a largely non-aggressive immune cell compartment1,2. The consequences of disturbing this balance include proximal inflammatory conditions, such as Crohn's disease, and systemic illnesses. This equilibrium is achieved in part through the induction of both effector and suppressor arms of the adaptive immune system. Helicobacter species induce T regulatory (Treg) and T follicular helper (TFH) cells under homeostatic conditions, but induce inflammatory T helper 17 (TH17) cells when induced Treg (iTreg) cells are compromised3,4. How Helicobacter and other gut bacteria direct T cells to adopt distinct functions remains poorly understood. Here we investigated the cells and molecular components required for iTreg cell differentiation. We found that antigen presentation by cells expressing RORγt, rather than by classical dendritic cells, was required and sufficient for induction of Treg cells. These RORγt+ cells-probably type 3 innate lymphoid cells and/or Janus cells5-require the antigen-presentation machinery, the chemokine receptor CCR7 and the TGFβ activator αv integrin. In the absence of any of these factors, there was expansion of pathogenic TH17 cells instead of iTreg cells, induced by CCR7-independent antigen-presenting cells. Thus, intestinal commensal microbes and their products target multiple antigen-presenting cells with pre-determined features suited to directing appropriate T cell differentiation programmes, rather than a common antigen-presenting cell that they endow with appropriate functions.
    DOI:  https://doi.org/10.1038/s41586-022-05089-y
  5. Nat Commun. 2022 Sep 08. 13(1): 5282
    Structure-function analysis of enterovirus protease 2A in complex with its essential host factor SETD3.
    Christine E Peters, Ursula Schulze-Gahmen, Manon Eckhardt, Gwendolyn M Jang, Jiewei Xu, Ernst H Pulido, Conner Bardine, Charles S Craik, Melanie Ott, Or Gozani, Kliment A Verba, Ruth Hüttenhain, Jan E Carette, Nevan J Krogan.
      Enteroviruses cause a number of medically relevant and widespread human diseases with no approved antiviral therapies currently available. Host-directed therapies present an enticing option for this diverse genus of viruses. We have previously identified the actin histidine methyltransferase SETD3 as a critical host factor physically interacting with the viral protease 2A. Here, we report the 3.5 Å cryo-EM structure of SETD3 interacting with coxsackievirus B3 2A at two distinct interfaces, including the substrate-binding surface within the SET domain. Structure-function analysis revealed that mutations of key residues in the SET domain resulted in severely reduced binding to 2A and complete protection from enteroviral infection. Our findings provide insight into the molecular basis of the SETD3-2A interaction and a framework for the rational design of host-directed therapeutics against enteroviruses.
    DOI:  https://doi.org/10.1038/s41467-022-32758-3
  6. Nat Commun. 2022 Sep 09. 13(1): 5312
    In vivo tumor immune microenvironment phenotypes correlate with inflammation and vasculature to predict immunotherapy response.
    Aditi Sahu, Kivanc Kose, Lukas Kraehenbuehl, Candice Byers, Aliya Holland, Teguru Tembo, Anthony Santella, Anabel Alfonso, Madison Li, Miguel Cordova, Melissa Gill, Christi Fox, Salvador Gonzalez, Piyush Kumar, Amber Weiching Wang, Nicholas Kurtansky, Pratik Chandrani, Shen Yin, Paras Mehta, Cristian Navarrete-Dechent, Gary Peterson, Kimeil King, Stephen Dusza, Ning Yang, Shuaitong Liu, William Phillips, Pascale Guitera, Anthony Rossi, Allan Halpern, Liang Deng, Melissa Pulitzer, Ashfaq Marghoob, Chih-Shan Jason Chen, Taha Merghoub, Milind Rajadhyaksha.
      Response to immunotherapies can be variable and unpredictable. Pathology-based phenotyping of tumors into 'hot' and 'cold' is static, relying solely on T-cell infiltration in single-time single-site biopsies, resulting in suboptimal treatment response prediction. Dynamic vascular events (tumor angiogenesis, leukocyte trafficking) within tumor immune microenvironment (TiME) also influence anti-tumor immunity and treatment response. Here, we report dynamic cellular-level TiME phenotyping in vivo that combines inflammation profiles with vascular features through non-invasive reflectance confocal microscopic imaging. In skin cancer patients, we demonstrate three main TiME phenotypes that correlate with gene and protein expression, and response to toll-like receptor agonist immune-therapy. Notably, phenotypes with high inflammation associate with immunostimulatory signatures and those with high vasculature with angiogenic and endothelial anergy signatures. Moreover, phenotypes with high inflammation and low vasculature demonstrate the best treatment response. This non-invasive in vivo phenotyping approach integrating dynamic vasculature with inflammation serves as a reliable predictor of response to topical immune-therapy in patients.
    DOI:  https://doi.org/10.1038/s41467-022-32738-7
  7. Immunity. 2022 Sep 02. pii: S1074-7613(22)00400-9. [Epub ahead of print]
    Induction of a colitogenic phenotype in Th1-like cells depends on interleukin-23 receptor signaling.
    Mathias Pawlak, David DeTomaso, Alexandra Schnell, Gerd Meyer Zu Horste, Youjin Lee, Jackson Nyman, Danielle Dionne, Brianna M L Regan, Vasundhara Singh, Toni Delorey, Markus A Schramm, Chao Wang, Antonia Wallrapp, Patrick R Burkett, Samantha J Riesenfeld, Ana C Anderson, Aviv Regev, Ramnik J Xavier, Nir Yosef, Vijay K Kuchroo.
      Interleukin-23 receptor plays a critical role in inducing inflammation and autoimmunity. Here, we report that Th1-like cells differentiated in vitro with IL-12 + IL-21 showed similar IL-23R expression to that of pathogenic Th17 cells using eGFP reporter mice. Fate mapping established that these cells did not transition through a Th17 cell state prior to becoming Th1-like cells, and we observed their emergence in vivo in the T cell adoptive transfer colitis model. Using IL-23R-deficient Th1-like cells, we demonstrated that IL-23R was required for the development of a highly colitogenic phenotype. Single-cell RNA sequencing analysis of intestinal T cells identified IL-23R-dependent genes in Th1-like cells that differed from those expressed in Th17 cells. The perturbation of one of these regulators (CD160) in Th1-like cells inhibited the induction of colitis. We thus uncouple IL-23R as a purely Th17 cell-specific factor and implicate IL-23R signaling as a pathogenic driver in Th1-like cells inducing tissue inflammation.
    Keywords:  IL-23; IL-23 receptor; T helper cell; Th1-like cell; autoimmunity; colitis; inflammation; inflammatory bowel disease; pre-clinical mouse model; single-cell RNA sequencing
    DOI:  https://doi.org/10.1016/j.immuni.2022.08.007
  8. Nat Commun. 2022 Sep 06. 13(1): 4981
    Lactate increases stemness of CD8 + T cells to augment anti-tumor immunity.
    Qiang Feng, Zhida Liu, Xuexin Yu, Tongyi Huang, Jiahui Chen, Jian Wang, Jonathan Wilhelm, Suxin Li, Jiwon Song, Wei Li, Zhichen Sun, Baran D Sumer, Bo Li, Yang-Xin Fu, Jinming Gao.
      Lactate is a key metabolite produced from glycolytic metabolism of glucose molecules, yet it also serves as a primary carbon fuel source for many cell types. In the tumor-immune microenvironment, effect of lactate on cancer and immune cells can be highly complex and hard to decipher, which is further confounded by acidic protons, a co-product of glycolysis. Here we show that lactate is able to increase stemness of CD8+ T cells and augments anti-tumor immunity. Subcutaneous administration of sodium lactate but not glucose to mice bearing transplanted MC38 tumors results in CD8+ T cell-dependent tumor growth inhibition. Single cell transcriptomics analysis reveals increased proportion of stem-like TCF-1-expressing CD8+ T cells among intra-tumoral CD3+ cells, a phenotype validated by in vitro lactate treatment of T cells. Mechanistically, lactate inhibits histone deacetylase activity, which results in increased acetylation at H3K27 of the Tcf7 super enhancer locus, leading to increased Tcf7 gene expression. CD8+ T cells in vitro pre-treated with lactate efficiently inhibit tumor growth upon adoptive transfer to tumor-bearing mice. Our results provide evidence for an intrinsic role of lactate in anti-tumor immunity independent of the pH-dependent effect of lactic acid, and might advance cancer immune therapy.
    DOI:  https://doi.org/10.1038/s41467-022-32521-8
  9. Nat Methods. 2022 Sep 05.
    A bead-based method for high-throughput mapping of the sequence- and force-dependence of T cell activation.
    Yinnian Feng, Xiang Zhao, Adam K White, K Christopher Garcia, Polly M Fordyce.
      Adaptive immunity relies on T lymphocytes that use αβ T cell receptors (TCRs) to discriminate among peptides presented by major histocompatibility complex molecules (pMHCs). Identifying pMHCs capable of inducing robust T cell responses will not only enable a deeper understanding of the mechanisms governing immune responses but could also have broad applications in diagnosis and treatment. T cell recognition of sparse antigenic pMHCs in vivo relies on biomechanical forces. However, in vitro screening methods test potential pMHCs without force and often at high (nonphysiological) pMHC densities and thus fail to predict potent agonists in vivo. Here, we present a technology termed BATTLES (biomechanically assisted T cell triggering for large-scale exogenous-pMHC screening) that uses biomechanical force to initiate T cell triggering for peptides and cells in parallel. BATTLES displays candidate pMHCs on spectrally encoded beads composed of a thermo-responsive polymer capable of applying shear loads to T cells, facilitating exploration of the force- and sequence-dependent landscape of T cell responses. BATTLES can be used to explore basic T cell mechanobiology and T cell-based immunotherapies.
    DOI:  https://doi.org/10.1038/s41592-022-01592-2
  10. Nat Commun. 2022 Sep 07. 13(1): 5117
    Beiging of perivascular adipose tissue regulates its inflammation and vascular remodeling.
    Yusuke Adachi, Kazutaka Ueda, Seitaro Nomura, Kaoru Ito, Manami Katoh, Mikako Katagiri, Shintaro Yamada, Masaki Hashimoto, Bowen Zhai, Genri Numata, Akira Otani, Munetoshi Hinata, Yuta Hiraike, Hironori Waki, Norifumi Takeda, Hiroyuki Morita, Tetsuo Ushiku, Toshimasa Yamauchi, Eiki Takimoto, Issei Komuro.
      Although inflammation plays critical roles in the development of atherosclerosis, its regulatory mechanisms remain incompletely understood. Perivascular adipose tissue (PVAT) has been reported to undergo inflammatory changes in response to vascular injury. Here, we show that vascular injury induces the beiging (brown adipose tissue-like phenotype change) of PVAT, which fine-tunes inflammatory response and thus vascular remodeling as a protective mechanism. In a mouse model of endovascular injury, macrophages accumulate in PVAT, causing beiging phenotype change. Inhibition of PVAT beiging by genetically silencing PRDM16, a key regulator to beiging, exacerbates inflammation and vascular remodeling following injury. Conversely, activation of PVAT beiging attenuates inflammation and pathological vascular remodeling. Single-cell RNA sequencing reveals that beige adipocytes abundantly express neuregulin 4 (Nrg4) which critically regulate alternative macrophage activation. Importantly, significant beiging is observed in the diseased aortic PVAT in patients with acute aortic dissection. Taken together, vascular injury induces the beiging of adjacent PVAT with macrophage accumulation, where NRG4 secreted from the beige PVAT facilitates alternative activation of macrophages, leading to the resolution of vascular inflammation. Our study demonstrates the pivotal roles of PVAT in vascular inflammation and remodeling and will open a new avenue for treating atherosclerosis.
    DOI:  https://doi.org/10.1038/s41467-022-32658-6
  11. Nature. 2022 Sep 07.
    Novel antigen presenting cell imparts Treg-dependent tolerance to gut microbiota.
    Blossom Akagbosu, Zakieh Tayyebi, Gayathri Shibu, Yoselin A Paucar Iza, Deeksha Deep, Yollanda Franco Parisotto, Logan Fisher, H Amalia Pasolli, Valentin Thevin, Rasa Elmentaite, Maximilian Knott, Saskia Hemmers, Lorenz Jahn, Christin Friedrich, Jacob Verter, Zhong-Min Wang, Marcel van den Brink, Georg Gasteiger, Thomas G P Grünewald, Julien C Marie, Christina Leslie, Alexander Y Rudensky, Chrysothemis C Brown.
      Establishing and maintaining tolerance to self- or innocuous foreign antigens is vital for preservation of organismal health. Within the thymus, medullary thymic epithelial cells (mTECs) expressing AutoImmune Regulator, Aire, play a critical role in self-tolerance through deletion of autoreactive T cells and promotion of thymic regulatory T (Treg) cell development1-4. Within weeks of birth, a separate wave of Treg cell differentiation occurs in the periphery, upon exposure to dietary and commensal microbiota derived antigens5-8, yet the cell types responsible for the generation of peripheral Treg (pTreg) cells are not known. Here we identified a new class of RORγt+ antigen-presenting cells (APC), dubbed Thetis cells (TCs), with transcriptional features of both mTECs and dendritic cells (DCs), comprising 4 major sub-groups (TC I-IV). We uncovered a developmental wave of TCs within intestinal lymph nodes during a critical early life window, coincident with the wave of pTreg cell differentiation. While TC I and III expressed the signature mTEC nuclear factor Aire, TC IV lacked Aire expression and were enriched for molecules required for pTreg generation, including the TGF-β activating integrin αvβ8. Loss of either MHCII or Itgb8 expression by TCs led to a profound impairment in intestinal pTreg differentiation, with ensuing colitis. In contrast, MHCII expression by RORγt+ group 3 innate lymphoid cells (ILC3) and classical DCs was neither sufficient nor required for pTreg generation, further implicating TC IV as the tolerogenic RORγt+ APC with an essential early life function. Our studies reveal parallel pathways for establishment of tolerance to self and foreign antigen within the thymus and periphery, respectively, marked by involvement of shared cellular and transcriptional programs.
    DOI:  https://doi.org/10.1038/s41586-022-05309-5
  12. Nat Commun. 2022 Sep 07. 13(1): 5261
    Bidirectional lysosome transport: a balancing act between ARL8 effectors.
    Agnieszka A Kendrick, Jenna R Christensen.
      
    DOI:  https://doi.org/10.1038/s41467-022-32965-y
  13. Cell Metab. 2022 Sep 06. pii: S1550-4131(22)00357-6. [Epub ahead of print]34(9): 1394-1409.e4
    3D chromatin maps of the human pancreas reveal lineage-specific regulatory architecture of T2D risk.
    HPAP Consortium
      Three-dimensional (3D) chromatin organization maps help dissect cell-type-specific gene regulatory programs. Furthermore, 3D chromatin maps contribute to elucidating the pathogenesis of complex genetic diseases by connecting distal regulatory regions and genetic risk variants to their respective target genes. To understand the cell-type-specific regulatory architecture of diabetes risk, we generated transcriptomic and 3D epigenomic profiles of human pancreatic acinar, alpha, and beta cells using single-cell RNA-seq, single-cell ATAC-seq, and high-resolution Hi-C of sorted cells. Comparisons of these profiles revealed differential A/B (open/closed) chromatin compartmentalization, chromatin looping, and transcriptional factor-mediated control of cell-type-specific gene regulatory programs. We identified a total of 4,750 putative causal-variant-to-target-gene pairs at 194 type 2 diabetes GWAS signals using pancreatic 3D chromatin maps. We found that the connections between candidate causal variants and their putative target effector genes are cell-type stratified and emphasize previously underappreciated roles for alpha and acinar cells in diabetes pathogenesis.
    Keywords:  3D chromatin maps; acinar cell; alpha cell; beta cell; islets of Langerhans; type 2 diabetes
    DOI:  https://doi.org/10.1016/j.cmet.2022.08.014
  14. J Leukoc Biol. 2022 Sep 08.
    Dectin-1 signaling in neutrophils up-regulates PD-L1 and triggers ROS-mediated suppression of CD4+ T cells.
    M Elizabeth Deerhake, Emre D Cardakli, Mari L Shinohara.
      Dectin-1 is known to drive proinflammatory cytokine production by macrophages and dendritic cells which promotes Th17 CD4+ T cell responses in the setting of fungal infection. However, the role of Dectin-1 signaling in neutrophils and its impact on CD4+ T cells is not well understood. In this study, we found that neutrophils stimulated with a Dectin-1 agonist diminish CD4+ T cell viability in a rapid and reactive oxygen species (ROS)-dependent manner. Furthermore, Dectin-1 promoted neutrophil PD-L1 expression via Syk and Card9 signaling, along with other immune-checkpoint factors in a neutrophil-biased manner. Although neutrophil PD-L1 did not significantly impact disease severity in experimental autoimmune encephalomyelitis (EAE), we found that CNS-infiltrated neutrophils potently up-regulate PD-L1 expression. Furthermore, a subset of PD-L1+ neutrophils was also found to express MHC-II during EAE. In summary, we found that Dectin-1 elicits a biphasic neutrophil response in which (1) T-cell suppressive ROS is followed by (2) up-regulation of PD-L1 expression. This response may serve to limit excess CD4+ T cell-driven inflammation in infection or autoimmunity while preserving host-defense functions of neutrophils. Summary sentence: Mechanisms by which Dectin-1 signaling in neutrophils promotes a cellular phenotype with T cell-suppressive properties.
    Keywords:  PD-L1; check-point molecule; dectin-1
    DOI:  https://doi.org/10.1002/JLB.3A0322-152RR
  15. Nat Commun. 2022 Sep 05. 13(1): 5226
    Molecular basis for polysaccharide recognition and modulated ATP hydrolysis by the O antigen ABC transporter.
    Nicholas Spellmon, Artur Muszyński, Ireneusz Górniak, Jiri Vlach, David Hahn, Parastoo Azadi, Jochen Zimmer.
      O antigens are ubiquitous protective extensions of lipopolysaccharides in the extracellular leaflet of the Gram-negative outer membrane. Following biosynthesis in the cytosol, the lipid-linked polysaccharide is transported to the periplasm by the WzmWzt ABC transporter. Often, O antigen secretion requires the chemical modification of its elongating terminus, which the transporter recognizes via a carbohydrate-binding domain (CBD). Here, using components from A. aeolicus, we identify the O antigen structure with methylated mannose or rhamnose as its cap. Crystal and cryo electron microscopy structures reveal how WzmWzt recognizes this cap between its carbohydrate and nucleotide-binding domains in a nucleotide-free state. ATP binding induces drastic conformational changes of its CBD, terminating interactions with the O antigen. ATPase assays and site directed mutagenesis reveal reduced hydrolytic activity upon O antigen binding, likely to facilitate polymer loading into the ABC transporter. Our results elucidate critical steps in the recognition and translocation of polysaccharides by ABC transporters.
    DOI:  https://doi.org/10.1038/s41467-022-32597-2
  16. Cell Metab. 2022 Sep 06. pii: S1550-4131(22)00356-4. [Epub ahead of print]34(9): 1227-1229
    Walking the high wire: How neurons maintain stability in the crossline of neurodegeneration.
    Matheus B Victor, Li-Huei Tsai.
      In this issue of Cell Metabolism, Traxler et al. report a metabolic switch in neurons that hinges on the critical balance of pyruvate kinase M (PKM) isoform ratios. Using directly induced neurons (iNs) derived from patients with Alzheimer's disease (AD), the work delineates the impact of an AD-specific switch from PKM1 to PKM2 onto neuronal resilience against neurodegeneration.
    DOI:  https://doi.org/10.1016/j.cmet.2022.08.013
  17. FASEB J. 2022 Oct;36(10): e22538
    Antipsychotic drugs induce vascular defects in hematopoietic organs.
    Zhao-Hua Deng, Jing Zhong, Hai-Lin Jiang, Hyun-Woo Jeong, Jian-Wei Chen, Ya-Hai Shu, Ming Tan, Ralf H Adams, Ke-Ping Xie, Qi Chen, Yang Liu.
      Antipsychotic agents are clinically utilized to treat schizophrenia and other mental disorders. These drugs induce neurological and metabolic side effects, but their influence on blood vessels remains largely unknown. Here, we show that haloperidol, one of the most frequently prescribed antipsychotic agents, induces vascular defects in bone marrow. Acute haloperidol treatment results in vascular dilation that is specific to hematopoietic organs. This vessel dilation is associated with disruption of hematopoiesis and hematopoietic stem/progenitor cells (HSPCs), both of which are reversible after haloperidol withdrawal. Mechanistically, haloperidol treatment blocked the secretion of vascular endothelial growth factor A (VEGF-A) from HSPCs. Genetic blockade of VEGF-A secretion from hematopoietic cells or inhibition of VEGFR2 in endothelial cells result in similar vessel dilation in bone marrow during regeneration after irradiation and transplantation. Conversely, VEGF-A gain of function rescues the bone marrow vascular defects induced by haloperidol treatment and irradiation. Our work reveals an unknown effect of antipsychotic agents on the vasculature and hematopoiesis with potential implications for drug application in clinic.
    Keywords:  VEGF; antipsychotic agents; bone marrow; haloperidol; hematopoietic stem cell; stem cell microenvironment; vascular endothelial cell
    DOI:  https://doi.org/10.1096/fj.202200862R
  18. Science. 2022 Sep 08. eabn5648
    The human disease gene LYSET is essential for lysosomal enzyme transport and viral infection.
    Christopher M Richards, Sabrina Jabs, Wenjie Qiao, Lauren D Varanese, Michaela Schweizer, Peter R Mosen, Nicholas M Riley, Malte Klüssendorf, James R Zengel, Ryan A Flynn, Arjun Rustagi, John C Widen, Christine E Peters, Yaw Shin Ooi, Xuping Xie, Pei-Yong Shi, Ralf Bartenschlager, Andreas S Puschnik, Matthew Bogyo, Carolyn R Bertozzi, Catherine A Blish, Dominic Winter, Claude M Nagamine, Thomas Braulke, Jan E Carette.
      Lysosomes are key degradative compartments of the cell. Transport to lysosomes relies on GlcNAc-1-phosphotransferase-mediated tagging of soluble enzymes with mannose 6-phosphate (M6P). GlcNAc-1-phosphotransferase deficiency leads to the severe lysosomal storage disorder mucolipidosis II (MLII). Several viruses require lysosomal cathepsins to cleave structural proteins and thus depend on functional GlcNAc-1-phosphotransferase. Here, we used genome-scale CRISPR screens to identify Lysosomal Enzyme Trafficking factor (LYSET) as essential for infection by cathepsin-dependent viruses including SARS-CoV-2. LYSET deficiency resulted in global loss of M6P tagging and mislocalization of GlcNAc-1-phosphotransferase from the Golgi complex to lysosomes. Lyset knockout mice exhibited MLII-like phenotypes and human pathogenic LYSET alleles failed to restore lysosomal sorting defects. Thus, LYSET is required for correct functioning of the M6P trafficking machinery, and mutations in LYSET can explain the phenotype of the associated disorder.
    DOI:  https://doi.org/10.1126/science.abn5648
  19. Nature. 2022 Sep 09.
    How cholesterol encourages a cell to bulk up.
      
    Keywords:  Cell biology
    DOI:  https://doi.org/10.1038/d41586-022-02773-x
  20. Nat Commun. 2022 Sep 03. 13(1): 5202
    Spermidine-mediated hypusination of translation factor EIF5A improves mitochondrial fatty acid oxidation and prevents non-alcoholic steatohepatitis progression.
    Jin Zhou, Jeremy Pang, Madhulika Tripathi, Jia Pei Ho, Anissa Anindya Widjaja, Shamini Guna Shekeran, Stuart Alexander Cook, Ayako Suzuki, Anna Mae Diehl, Enrico Petretto, Brijesh Kumar Singh, Paul Michael Yen.
      Spermidine is a natural polyamine that has health benefits and extends life span in several species. Deoxyhypusine synthase (DHPS) and deoxyhypusine hydroxylase (DOHH) are key enzymes that utilize spermidine to catalyze the post-translational hypusination of the translation factor EIF5A (EIF5AH). Here, we have found that hepatic DOHH mRNA expression is decreased in patients and mice with non-alcoholic steatohepatitis (NASH), and hepatic cells treated with fatty acids. The mouse and cell culture models of NASH have concomitant decreases in Eif5aH and mitochondrial protein synthesis which leads to lower mitochondrial activity and fatty acid β-oxidation. Spermidine treatment restores EIF5AH, partially restores protein synthesis and mitochondrial function in NASH, and prevents NASH progression in vivo. Thus, the disrupted DHPS-DOHH-EIF5AH pathway during NASH represents a therapeutic target to increase hepatic protein synthesis and mitochondrial fatty acid oxidation (FAO) and prevent NASH progression.
    DOI:  https://doi.org/10.1038/s41467-022-32788-x
  21. Nat Commun. 2022 Sep 05. 13(1): 5225
    Potential solutions for manufacture of CAR T cells in cancer immunotherapy.
    Ulrich Blache, Georg Popp, Anna Dünkel, Ulrike Koehl, Stephan Fricke.
      
    DOI:  https://doi.org/10.1038/s41467-022-32866-0
  22. Commun Biol. 2022 Sep 05. 5(1): 911
    Clonal dynamics underlying the skewed CD4/CD8 ratio of mouse thymocytes revealed by TCR-independent barcoding.
    Norimasa Iwanami, Malte Petersen, Dagmar Diekhoff, Thomas Boehm.
      T cell differentiation in the thymus generates CD4+ helper and cytotoxic CD8+ cells as the two principal T cell lineages. Curiously, at the end of this complex selection process, CD4+ cells invariably outnumber CD8+ cells. Here, we examine the dynamics of repertoire formation and the emergence of the skewed CD4/CD8 ratio using high-resolution endogenous CRISPR/Cas9 barcoding that indelibly marks immature T cells at the DN2/DN3 pre-TCR stage. In wild-type mice, greater clone size of CD4+ cells and an intrinsically greater probability of Tcr β clonotypes for pMHCII interactions are major contributors to the skewed CD4/CD8 ratio. Clonal perturbations of thymocyte differentiation following the precocious expression of a rearranged iNKT invariant TCR α chain are due to loss of Tcr β clonotypes from the CD4 lineage-committed pre-selection repertoire. The present barcoding scheme offers a novel means to examine the clonal dynamics of lymphocyte differentiation orthogonal to that using TCR clonotypes.
    DOI:  https://doi.org/10.1038/s42003-022-03870-3
  23. Nat Commun. 2022 Sep 08. 13(1): 5281
    Regulation associated modules reflect 3D genome modularity associated with chromatin activity.
    Lina Zheng, Wei Wang.
      The 3D genome has been shown to be organized into modules including topologically associating domains (TADs) and compartments that are primarily defined by spatial contacts from Hi-C. There exists a gap to investigate whether and how the spatial modularity of the chromatin is related to the functional modularity resulting from chromatin activity. Despite histone modifications reflecting chromatin activity, inferring spatial modularity of the genome directly from the histone modification patterns has not been well explored. Here, we report that histone modifications show a modular pattern (referred to as regulation associated modules, RAMs) that reflects spatial chromatin modularity. Enhancer-promoter interactions, loop anchors, super-enhancer clusters and extrachromosomal DNAs (ecDNAs) are found to occur more often within the same RAMs than within the same TADs. Consistently, compared to the TAD boundaries, deletions of RAM boundaries perturb the chromatin structure more severely (may even cause cell death) and somatic variants in cancer samples are more enriched in RAM boundaries. These observations suggest that RAMs reflect a modular organization of the 3D genome at a scale better aligned with chromatin activity, providing a bridge connecting the structural and functional modularity of the genome.
    DOI:  https://doi.org/10.1038/s41467-022-32911-y
  24. Nat Commun. 2022 Sep 03. 13(1): 5187
    Taz protects hematopoietic stem cells from an aging-dependent decrease in PU.1 activity.
    Kyung Mok Kim, Anna Mura-Meszaros, Marie Tollot, Murali Shyam Krishnan, Marco Gründl, Laura Neubert, Marco Groth, Alejo Rodriguez-Fraticelli, Arthur Flohr Svendsen, Stefano Campaner, Nico Andreas, Thomas Kamradt, Steve Hoffmann, Fernando D Camargo, Florian H Heidel, Leonid V Bystrykh, Gerald de Haan, Björn von Eyss.
      Specific functions of the immune system are essential to protect us from infections caused by pathogens such as viruses and bacteria. However, as we age, the immune system shows a functional decline that can be attributed in large part to age-associated defects in hematopoietic stem cells (HSCs)-the cells at the apex of the immune cell hierarchy. Here, we find that the Hippo pathway coactivator TAZ is potently induced in old HSCs and protects these cells from functional decline. We identify Clca3a1 as a TAZ-induced gene that allows us to trace TAZ activity in vivo. Using CLCA3A1 as a marker, we can isolate "young-like" HSCs from old mice. Mechanistically, Taz acts as coactivator of PU.1 and to some extent counteracts the gradual loss of PU.1 expression during HSC aging. Our work thus uncovers an essential role for Taz in a previously undescribed fail-safe mechanism in aging HSCs.
    DOI:  https://doi.org/10.1038/s41467-022-32970-1
  25. Nat Commun. 2022 Sep 09. 13(1): 5313
    CAR-T cell therapy-related cytokine release syndrome and therapeutic response is modulated by the gut microbiome in hematologic malignancies.
    Yongxian Hu, Jingjing Li, Fang Ni, Zhongli Yang, Xiaohua Gui, Zhiwei Bao, Houli Zhao, Guoqing Wei, Yiyun Wang, Mingming Zhang, Ruimin Hong, Linqin Wang, Wenjun Wu, Mohamad Mohty, Arnon Nagler, Alex H Chang, Marcel R M van den Brink, Ming D Li, He Huang.
      Immunotherapy utilizing chimeric antigen receptor T cell (CAR-T) therapy holds promise for hematologic malignancies, however, response rates and associated immune-related adverse effects widely vary among patients. Here we show, by comparing diversity and composition of the gut microbiome during different CAR-T therapeutic phases in the clinical trial ChiCTR1800017404, that the gut flora characteristically differs among patients and according to treatment stages, and might also reflect patient response to therapy in relapsed/refractory multiple myeloma (MM; n = 43), acute lympholastic leukemia (ALL; n = 23) and non-Hodgkin lymphoma (NHL; n = 12). We observe significant temporal differences in diversity and abundance of Bifidobacterium, Prevotella, Sutterella, and Collinsella between MM patients in complete remission (n = 24) and those in partial remission (n = 11). Furthermore, we find that patients with severe cytokine release syndrome present with higher abundance of Bifidobacterium, Leuconostoc, Stenotrophomonas, and Staphylococcus, which is reproducible in an independent cohort of 38 MM patients. This study has important implications for understanding the biological role of the microbiome in CAR-T treatment responsiveness of hematologic malignancy patients, and may guide therapeutic intervention to increase efficacy. The success rate of CAR-T cell therapy is high in blood cancers, yet individual patient characteristics might reduce therapeutic benefit. Here we show that therapeutic response in MM, ALL and NHL, and occurrence of severe cytokine release syndrome in multiple myeloma are associated with specific gut microbiome alterations.
    DOI:  https://doi.org/10.1038/s41467-022-32960-3
  26. Nature. 2022 Sep 07.
    Gut-Brain Circuits for Fat Preference.
    Mengtong Li, Hwei-Ee Tan, Zhengyuan Lu, Katherine S Tsang, Ashley J Chung, Charles S Zuker.
      The perception of fat evokes strong appetitive and consummatory responses1. Here we show that fat stimuli can induce behavioural attraction even in the absence of a functional taste system2,3. We demonstrate that fat acts post-ingestively via the gut-brain axis to drive preference for fat. Using single-cell data, we identified the vagal neurons responding to intestinal delivery of fat, and showed that genetic silencing of this gut-to-brain circuit abolished the development of fat preference. Next, we compared the gut-to-brain pathways driving preference for fat versus sugar4, and uncovered two parallel systems, one functioning as a general sensor of essential nutrients, responding to intestinal stimulation with sugar, fat and amino acids, while the other is activated only by fat stimuli. Lastly, we engineered animals lacking candidate receptors detecting the presence of intestinal fat, and validated their role as the mediators of gut-to-brain fat-evoked responses. Together, these findings revealed distinct cells and receptors using the gut-brain axis as a fundamental conduit for the development of fat preference.
    DOI:  https://doi.org/10.1038/s41586-022-05266-z
  27. iScience. 2022 Sep 16. 25(9): 104920
    Mitochondrial protein synthesis and the bioenergetic cost of neurodevelopment.
    Pernille Bülow, Anupam Patgiri, Victor Faundez.
      The human brain consumes five orders of magnitude more energy than the sun by unit of mass and time. This staggering bioenergetic cost serves mostly synaptic transmission and actin cytoskeleton dynamics. The peak of both brain bioenergetic demands and the age of onset for neurodevelopmental disorders is approximately 5 years of age. This correlation suggests that defects in the machinery that provides cellular energy would be causative and/or consequence of neurodevelopmental disorders. We explore this hypothesis from the perspective of the machinery required for the synthesis of the electron transport chain, an ATP-producing and NADH-consuming enzymatic cascade. The electron transport chain is constituted by nuclear- and mitochondrial-genome-encoded subunits. These subunits are synthesized by the 80S and the 55S ribosomes, which are segregated to the cytoplasm and the mitochondrial matrix, correspondingly. Mitochondrial protein synthesis by the 55S ribosome is the rate-limiting step in the synthesis of electron transport chain components, suggesting that mitochondrial protein synthesis is a bottleneck for tissues with high bionergetic demands. We discuss genetic defects in the human nuclear and mitochondrial genomes that affect these protein synthesis machineries and cause a phenotypic spectrum spanning autism spectrum disorders to neurodegeneration during neurodevelopment. We propose that dysregulated mitochondrial protein synthesis is a chief, yet understudied, causative mechanism of neurodevelopmental and behavioral disorders.
    Keywords:  Biological Sciences; Cell Biology; Neuroscience
    DOI:  https://doi.org/10.1016/j.isci.2022.104920
  28. Cell Metab. 2022 Sep 06. pii: S1550-4131(22)00347-3. [Epub ahead of print]34(9): 1264-1279.e8
    Extracellular vesicles mediate the communication of adipose tissue with brain and promote cognitive impairment associated with insulin resistance.
    Jin Wang, Liang Li, Zhou Zhang, Xuhong Zhang, Ye Zhu, Chenyu Zhang, Yan Bi.
      Type 2 diabetes with obesity-related insulin resistance as the main manifestation is associated with an increased risk of cognitive impairment. Adipose tissue plays an important role in this process. Here, we demonstrated that adipose tissue-derived extracellular vesicles (EVs) and their cargo microRNAs (miRNAs) mediate inter-organ communication between adipose tissue and the brain, which can be transferred into the brain in a membrane protein-dependent manner and enriched in neurons, especially in the hippocampus. Further investigation suggests that adipose tissue-derived EVs from high-fat diet (HFD)-fed mice or patients with diabetes induce remarkable synaptic loss and cognitive impairment. Depletion of miRNA cargo in these EVs significantly alleviates their detrimental effects on cognitive function. Collectively, these data suggest that targeting adipose tissue-derived EVs or their cargo miRNAs may provide a promising strategy for pharmaceutical interventions for cognitive impairment in diabetes.
    Keywords:  adipose tissue; cognitive impairment; extracellular vesicles; insulin resistance; miRNA; obesity; type 2 diabetes
    DOI:  https://doi.org/10.1016/j.cmet.2022.08.004
  29. JCI Insight. 2022 Sep 08. pii: e153033. [Epub ahead of print]7(17):
    Pathological MAPK activation-mediated lymphatic basement membrane disruption causes lymphangiectasia that is treatable with ravoxertinib.
    Harish P Janardhan, Karen Dresser, Lloyd Hutchinson, Chinmay M Trivedi.
      Lymphangiectasia, an anomalous dilation of lymphatic vessels first described in the 17th century, is frequently associated with chylous effusion, respiratory failure, and high mortality in young patients, yet the underlying molecular pathogenesis and effective treatments remain elusive. Here, we identify an unexpected causal link between MAPK activation and defective development of the lymphatic basement membrane that drives lymphangiectasia. Human pathological tissue samples from patients diagnosed with lymphangiectasia revealed sustained MAPK activation within lymphatic endothelial cells. Endothelial KRASG12D-mediated sustained MAPK activation in newborn mice caused severe pulmonary and intercostal lymphangiectasia, accumulation of chyle in the pleural space, and complete lethality. Pathological activation of MAPK in murine vasculature inhibited the Nfatc1-dependent genetic program required for laminin interactions, collagen crosslinking, and anchoring fibril formation, driving defective development of the lymphatic basement membrane. Treatment with ravoxertinib, a pharmacological inhibitor of MAPK, reverses nuclear-to-cytoplasmic localization of Nfatc1, basement membrane development defects, lymphangiectasia, and chyle accumulation, ultimately improving survival of endothelial KRAS mutant neonatal mice. These results reveal defective lymphatic basement membrane assembly and composition as major causes of thoracic lymphangiectasia and provide a potential treatment.
    Keywords:  Cardiovascular disease; Development; Lymph; Mouse models; Vascular Biology
    DOI:  https://doi.org/10.1172/jci.insight.153033
  30. Nat Commun. 2022 Sep 08. 13(1): 5296
    Biomarker correlates with response to NY-ESO-1 TCR T cells in patients with synovial sarcoma.
    Alexandra Gyurdieva, Stefan Zajic, Ya-Fang Chang, E Andres Houseman, Shan Zhong, Jaegil Kim, Michael Nathenson, Thomas Faitg, Mary Woessner, David C Turner, Aisha N Hasan, John Glod, Rosandra N Kaplan, Sandra P D'Angelo, Dejka M Araujo, Warren A Chow, Mihaela Druta, George D Demetri, Brian A Van Tine, Stephan A Grupp, Gregg D Fine, Ioanna Eleftheriadou.
      Autologous T cells transduced to express a high affinity T-cell receptor specific to NY-ESO-1 (letetresgene autoleucel, lete-cel) show promise in the treatment of metastatic synovial sarcoma, with 50% overall response rate. The efficacy of lete-cel treatment in 45 synovial sarcoma patients (NCT01343043) has been previously reported, however, biomarkers predictive of response and resistance remain to be better defined. This post-hoc analysis identifies associations of response to lete-cel with lymphodepleting chemotherapy regimen (LDR), product attributes, cell expansion, cytokines, and tumor gene expression. Responders have higher IL-15 levels pre-infusion (p = 0.011) and receive a higher number of transduced effector memory (CD45RA- CCR7-) CD8 + cells per kg (p = 0.039). Post-infusion, responders have increased IFNγ, IL-6, and peak cell expansion (p < 0.01, p < 0.01, and p = 0.016, respectively). Analysis of tumor samples post-treatment illustrates lete-cel infiltration and a decrease in expression of macrophage genes, suggesting remodeling of the tumor microenvironment. Here we report potential predictive and pharmacodynamic markers of lete-cel response that may inform LDR, cell dose, and strategies to enhance anticancer efficacy.
    DOI:  https://doi.org/10.1038/s41467-022-32491-x
  31. Nature. 2022 Sep 08.
    Did this gene give modern human brains their edge?
    Sara Reardon.
      
    DOI:  https://doi.org/10.1038/d41586-022-02895-2
  32. Nat Commun. 2022 Sep 03. 13(1): 5203
    The nucleolus is the site for inflammatory RNA decay during infection.
    Taeyun A Lee, Heonjong Han, Ahsan Polash, Seok Keun Cho, Ji Won Lee, Eun A Ra, Eunhye Lee, Areum Park, Sujin Kang, Junhee L Choi, Ji Hyun Kim, Ji Eun Lee, Kyung-Won Min, Seong Wook Yang, Markus Hafner, Insuk Lee, Je-Hyun Yoon, Sungwook Lee, Boyoun Park.
      Inflammatory cytokines are key signaling molecules that can promote an immune response, thus their RNA turnover must be tightly controlled during infection. Most studies investigate the RNA decay pathways in the cytosol or nucleoplasm but never focused on the nucleolus. Although this organelle has well-studied roles in ribosome biogenesis and cellular stress sensing, the mechanism of RNA decay within the nucleolus is not completely understood. Here, we report that the nucleolus is an essential site of inflammatory pre-mRNA instability during infection. RNA-sequencing analysis reveals that not only do inflammatory genes have higher intronic read densities compared with non-inflammatory genes, but their pre-mRNAs are highly enriched in nucleoli during infection. Notably, nucleolin (NCL) acts as a guide factor for recruiting cytosine or uracil (C/U)-rich sequence-containing inflammatory pre-mRNAs and the Rrp6-exosome complex to the nucleolus through a physical interaction, thereby enabling targeted RNA delivery to Rrp6-exosomes and subsequent degradation. Consequently, Ncl depletion causes aberrant hyperinflammation, resulting in a severe lethality in response to LPS. Importantly, the dynamics of NCL post-translational modifications determine its functional activity in phases of LPS. This process represents a nucleolus-dependent pathway for maintaining inflammatory gene expression integrity and immunological homeostasis during infection.
    DOI:  https://doi.org/10.1038/s41467-022-32856-2
  33. Sci Adv. 2022 Sep 09. 8(36): eabg3203
    A neurogenetic mechanism of experience-dependent suppression of aggression.
    Kenichi Ishii, Matteo Cortese, Xubo Leng, Maxim N Shokhirev, Kenta Asahina.
      Aggression is an ethologically important social behavior, but excessive aggression can be detrimental to fitness. Social experiences among conspecific individuals reduce aggression in many species, the mechanism of which is largely unknown. We found that loss-of-function mutation of nervy (nvy), a Drosophila homolog of vertebrate myeloid translocation genes (MTGs), increased aggressiveness only in socially experienced flies and that this could be reversed by neuronal expression of human MTGs. A subpopulation of octopaminergic/tyraminergic neurons labeled by nvy was specifically required for such social experience-dependent suppression of aggression, in both males and females. Cell type-specific transcriptomic analysis of these neurons revealed aggression-controlling genes that are likely downstream of nvy. Our results illustrate both genetic and neuronal mechanisms by which the nervous system suppresses aggression in a social experience-dependent manner, a poorly understood process that is considered important for maintaining the fitness of animals.
    DOI:  https://doi.org/10.1126/sciadv.abg3203
  34. Sci Adv. 2022 Sep 09. 8(36): eabm2427
    Pronounced sequence specificity of the TET enzyme catalytic domain guides its cellular function.
    Mirunalini Ravichandran, Dominik Rafalski, Claudia I Davies, Oscar Ortega-Recalde, Xinsheng Nan, Cassandra R Glanfield, Annika Kotter, Katarzyna Misztal, Andrew H Wang, Marek Wojciechowski, Michał Rażew, Issam M Mayyas, Olga Kardailsky, Uwe Schwartz, Krzysztof Zembrzycki, Ian M Morison, Mark Helm, Dieter Weichenhan, Renata Z Jurkowska, Felix Krueger, Christoph Plass, Martin Zacharias, Matthias Bochtler, Timothy A Hore, Tomasz P Jurkowski.
      TET (ten-eleven translocation) enzymes catalyze the oxidation of 5-methylcytosine bases in DNA, thus driving active and passive DNA demethylation. Here, we report that the catalytic domain of mammalian TET enzymes favor CGs embedded within basic helix-loop-helix and basic leucine zipper domain transcription factor-binding sites, with up to 250-fold preference in vitro. Crystal structures and molecular dynamics calculations show that sequence preference is caused by intrasubstrate interactions and CG flanking sequence indirectly affecting enzyme conformation. TET sequence preferences are physiologically relevant as they explain the rates of DNA demethylation in TET-rescue experiments in culture and in vivo within the zygote and germ line. Most and least favorable TET motifs represent DNA sites that are bound by methylation-sensitive immediate-early transcription factors and octamer-binding transcription factor 4 (OCT4), respectively, illuminating TET function in transcriptional responses and pluripotency support.
    DOI:  https://doi.org/10.1126/sciadv.abm2427
  35. Nat Commun. 2022 Sep 05. 13(1): 5222
    Allosteric inhibition of HTRA1 activity by a conformational lock mechanism to treat age-related macular degeneration.
    Stefan Gerhardy, Mark Ultsch, Wanjian Tang, Evan Green, Jeffrey K Holden, Wei Li, Alberto Estevez, Chris Arthur, Irene Tom, Alexis Rohou, Daniel Kirchhofer.
      The trimeric serine protease HTRA1 is a genetic risk factor associated with geographic atrophy (GA), a currently untreatable form of age-related macular degeneration. Here, we describe the allosteric inhibition mechanism of HTRA1 by a clinical Fab fragment, currently being evaluated for GA treatment. Using cryo-EM, X-ray crystallography and biochemical assays we identify the exposed LoopA of HTRA1 as the sole Fab epitope, which is approximately 30 Å away from the active site. The cryo-EM structure of the HTRA1:Fab complex in combination with molecular dynamics simulations revealed that Fab binding to LoopA locks HTRA1 in a non-competent conformational state, incapable of supporting catalysis. Moreover, grafting the HTRA1-LoopA epitope onto HTRA2 and HTRA3 transferred the allosteric inhibition mechanism. This suggests a conserved conformational lock mechanism across the HTRA family and a critical role of LoopA for catalysis, which was supported by the reduced activity of HTRA1-3 upon LoopA deletion or perturbation. This study reveals the long-range inhibition mechanism of the clinical Fab and identifies an essential function of the exposed LoopA for activity of HTRA family proteases.
    DOI:  https://doi.org/10.1038/s41467-022-32760-9
  36. Cell Rep. 2022 Sep 06. pii: S2211-1247(22)01130-5. [Epub ahead of print]40(10): 111306
    Genetic- and diet-induced ω-3 fatty acid enrichment enhances TRPV4-mediated vasodilation in mice.
    Rebeca Caires, Tessa A C Garrud, Luis O Romero, Carlos Fernández-Peña, Valeria Vásquez, Jonathan H Jaggar, Julio F Cordero-Morales.
      TRPV4 channel activation in endothelial cells leads to vasodilation, while impairment of TRPV4 activity is implicated in vascular dysfunction. Strategies that increase TRPV4 activity could enhance vasodilation and ameliorate vascular disorders. Here, we show that supplementation with eicosapentaenoic acid (EPA), an ω-3 polyunsaturated fatty acid known to have beneficial cardiovascular effects, increases TRPV4 activity in human endothelial cells of various vascular beds. Mice carrying the C. elegans FAT-1 enzyme, which converts ω-6 to ω-3 polyunsaturated fatty acids, display higher EPA content and increased TRPV4-mediated vasodilation in mesenteric arteries. Likewise, mice fed an EPA-enriched diet exhibit enhanced and prolonged TRPV4-dependent vasodilation in an endothelial cell-specific manner. We also show that EPA supplementation reduces TRPV4 desensitization, which contributes to the prolonged vasodilation. Neutralization of positive charges in the TRPV4 N terminus impairs the effect of EPA on channel desensitization. These findings highlight the beneficial effects of manipulating fatty acid content to enhance TRPV4-mediated vasodilation.
    Keywords:  CP: Metabolism; EPA; LC-MS; TRPV4; desensitization; eicosapentaenoic acid; electrophysiology; endothelial cells; fat-1 transgenic mice; myography; omega-3 PUFA; vasodilation
    DOI:  https://doi.org/10.1016/j.celrep.2022.111306
  37. Nature. 2022 Sep 07.
    Brainstem ADCYAP1+ neurons control multiple aspects of sickness behaviour.
    Anoj Ilanges, Rani Shiao, Jordan Shaked, Ji-Dung Luo, Xiaofei Yu, Jeffrey M Friedman.
      Infections induce a set of pleiotropic responses in animals, including anorexia, adipsia, lethargy and changes in temperature, collectively termed sickness behaviours1. Although these responses have been shown to be adaptive, the underlying neural mechanisms have not been elucidated2-4. Here we use of a set of unbiased methodologies to show that a specific subpopulation of neurons in the brainstem can control the diverse responses to a bacterial endotoxin (lipopolysaccharide (LPS)) that potently induces sickness behaviour. Whole-brain activity mapping revealed that subsets of neurons in the nucleus of the solitary tract (NTS) and the area postrema (AP) acutely express FOS after LPS treatment, and we found that subsequent reactivation of these specific neurons in FOS2A-iCreERT2 (also known as TRAP2) mice replicates the behavioural and thermal component of sickness. In addition, inhibition of LPS-activated neurons diminished all of the behavioural responses to LPS. Single-nucleus RNA sequencing of the NTS-AP was used to identify LPS-activated neural populations, and we found that activation of ADCYAP1+ neurons in the NTS-AP fully recapitulates the responses elicited by LPS. Furthermore, inhibition of these neurons significantly diminished the anorexia, adipsia and locomotor cessation seen after LPS injection. Together these studies map the pleiotropic effects of LPS to a neural population that is both necessary and sufficient for canonical elements of the sickness response, thus establishing a critical link between the brain and the response to infection.
    DOI:  https://doi.org/10.1038/s41586-022-05161-7
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