bims-nimamd Biomed News
on Neuroimmunity and neuroinflammation in ageing and metabolic disease
Issue of 2023–04–16
48 papers selected by
Fawaz Alzaïd, Sorbonne Université
  1. Structural insights into how augmin augments the mitotic spindle.
  2. The problem of selection bias in studies of pre-mRNA splicing.
  3. Genome-wide CRISPR screens identify ILF3 as a mediator of mTORC1-dependent amino acid sensing.
  4. Restoring bone marrow niche function rejuvenates aged hematopoietic stem cells by reactivating the DNA Damage Response.
  5. Embryonic keratin19+ progenitors generate multiple functionally distinct progeny to maintain epithelial diversity in the adult thymus medulla.
  6. Spatiotemporally resolved transcriptomics reveals the subcellular RNA kinetic landscape.
  7. Aberrant activation of TCL1A promotes stem cell expansion in clonal haematopoiesis.
  8. Tenascin C+ papillary fibroblasts facilitate neuro-immune interaction in a mouse model of psoriasis.
  9. The scverse project provides a computational ecosystem for single-cell omics data analysis.
  10. A bacterial autotransporter impairs innate immune responses by targeting the transcription factor TFE3.
  11. A Cdk5-derived peptide inhibits Cdk5/p25 activity and improves neurodegenerative phenotypes.
  12. The origins and functional effects of postzygotic mutations throughout the human life span.
  13. TBC1D15 drives regeneration of acutely damaged lysosomes.
  14. Low-dose IL-2 enhances the generation of IL-10-producing immunoregulatory B cells.
  15. Mutation rates across species.
  16. Cryo-EM structures of mitochondrial ABC transporter ABCB10 in apo and biliverdin-bound form.
  17. Expansion of circulating stem-like CD8+ T cells by adding CD122-directed IL-2 complexes to radiation and anti-PD1 therapies in mice.
  18. Circulating blood eNAMPT drives the circadian rhythms in locomotor activity and energy expenditure.
  19. Modes of type 2 immune response initiation.
  20. Lipid droplets are intracellular mechanical stressors that impair hepatocyte function.
  21. Hypoimmune anti-CD19 chimeric antigen receptor T cells provide lasting tumor control in fully immunocompetent allogeneic humanized mice.
  22. Characterization of altered molecular mechanisms in Parkinson's disease through cell type-resolved multiomics analyses.
  23. A genome-wide optical pooled screen reveals regulators of cellular antiviral responses.
  24. Positive selection of somatically mutated clones identifies adaptive pathways in metabolic liver disease.
  25. FADS1-arachidonic acid axis enhances arachidonic acid metabolism by altering intestinal microecology in colorectal cancer.
  26. Lentinan confers protection against type 1 diabetes by inducing regulatory T cell in spontaneous non-obese diabetic mice.
  27. Uncovering biology by single-cell proteomics.
  28. Deregulation of ER-mitochondria contact formation and mitochondrial calcium homeostasis mediated by VDAC in fragile X syndrome.
  29. CTLA4 depletes T cell endogenous and trogocytosed B7 ligands via cis-endocytosis.
  30. Pathogen metabolite checkpoint: NHR on guard.
  31. Tracking tumor-specific CD8+ T cell responses.
  32. Previously uncharacterized rectangular bacterial structures in the dolphin mouth.
  33. Type 2 neuroimmune circuits in the shaping of physiology.
  34. Specialized septins.
  35. Inducible expression of interleukin-12 augments the efficacy of affinity-tuned chimeric antigen receptors in murine solid tumor models.
  36. Iron regulation in ferroptosis.
  37. Priming a vascular-selective cytokine response permits CD8+ T-cell entry into tumors.
  38. DT-109 ameliorates nonalcoholic steatohepatitis in nonhuman primates.
  39. Dandelion uses the single-cell adaptive immune receptor repertoire to explore lymphocyte developmental origins.
  40. High ploidy large cytoplasmic megakaryocytes are hematopoietic stem cells regulators and essential for platelet production.
  41. Trimming the genomic fat: minimising and re-functionalising genomes using synthetic biology.
  42. The intratumoral microbiota: From microniches to single cells.
  43. Ageing studies in five animals suggest how to reverse decline.
  44. Inflammatory signals from fatty bone marrow support DNMT3A driven clonal hematopoiesis.
  45. IDH3γ functions as a redox switch regulating mitochondrial energy metabolism and contractility in the heart.
  46. Defective import of mitochondrial metabolic enzyme elicits ectopic metabolic stress.
  47. Noncoding translation mitigation.
  48. Metabolism in type 2 immune responses.
  1. Nat Commun. 2023 Apr 13. 14(1): 2073
    Structural insights into how augmin augments the mitotic spindle.
    Szymon W Manka.
      
    DOI:  https://doi.org/10.1038/s41467-023-37625-3
  2. Nat Commun. 2023 Apr 08. 14(1): 1966
    The problem of selection bias in studies of pre-mRNA splicing.
    Zachary W Dwyer, Jeffrey A Pleiss.
      
    DOI:  https://doi.org/10.1038/s41467-023-37650-2
  3. Nat Cell Biol. 2023 Apr 10.
    Genome-wide CRISPR screens identify ILF3 as a mediator of mTORC1-dependent amino acid sensing.
    Guokai Yan, Jinxin Yang, Wen Li, Ao Guo, Jialiang Guan, Ying Liu.
      The mechanistic target of rapamycin complex 1 (mTORC1) is an essential hub that integrates nutrient signals and coordinates metabolism to control cell growth. Amino acid signals are detected by sensor proteins and relayed to the GATOR2 and GATOR1 complexes to control mTORC1 activity. Here we perform genome-wide CRISPR/Cas9 screens, coupled with an assay for mTORC1 activity based on fluorescence-activated cell sorting analysis of pS6, to identify potential regulators of mTORC1-dependent amino acid sensing. We then focus on interleukin enhancer binding factor 3 (ILF3), one of the candidate genes from the screen. ILF3 tethers the GATOR complexes to lysosomes to control mTORC1. Adding a lysosome-targeting sequence to the GATOR2 component WDR24 bypasses the requirement for ILF3 to modulate amino-acid-dependent mTORC1 signalling. ILF3 plays an evolutionarily conserved role in human and mouse cells, and in worms to regulate the mTORC1 pathway, control autophagy activity and modulate the ageing process.
    DOI:  https://doi.org/10.1038/s41556-023-01123-x
  4. Nat Commun. 2023 Apr 10. 14(1): 2018
    Restoring bone marrow niche function rejuvenates aged hematopoietic stem cells by reactivating the DNA Damage Response.
    Pradeep Ramalingam, Michael C Gutkin, Michael G Poulos, Taylor Tillery, Chelsea Doughty, Agatha Winiarski, Ana G Freire, Shahin Rafii, David Redmond, Jason M Butler.
      Aging associated defects within stem cell-supportive niches contribute towards age-related decline in stem cell activity. However, mechanisms underlying age-related niche defects, and whether restoring niche function can improve stem cell fitness, remain unclear. Here, we sought to determine whether aged blood stem cell function can be restored by rejuvenating their supportive niches within the bone marrow (BM). We identify Netrin-1 as a critical regulator of BM niche cell aging. Niche-specific deletion of Netrin-1 induces premature aging phenotypes within the BM microenvironment, while supplementation of aged mice with Netrin-1 rejuvenates aged niche cells and restores competitive fitness of aged blood stem cells to youthful levels. We show that Netrin-1 plays an essential role in maintaining active DNA damage responses (DDR), and that aging-associated decline in niche-derived Netrin-1 results in DNA damage accumulation within the BM microenvironment. We show that Netrin-1 supplementation is sufficient to resolve DNA damage and restore regenerative potential of the aged BM niche and blood stem cells to endure serial chemotherapy regimens.
    DOI:  https://doi.org/10.1038/s41467-023-37783-4
  5. Nat Commun. 2023 Apr 12. 14(1): 2066
    Embryonic keratin19+ progenitors generate multiple functionally distinct progeny to maintain epithelial diversity in the adult thymus medulla.
    Beth Lucas, Andrea J White, Fabian Klein, Clara Veiga-Villauriz, Adam Handel, Andrea Bacon, Emilie J Cosway, Kieran D James, Sonia M Parnell, Izumi Ohigashi, Yousuke Takahama, William E Jenkinson, Georg A Hollander, Wei-Yu Lu, Graham Anderson.
      The thymus medulla is a key site for immunoregulation and tolerance, and its functional specialisation is achieved through the complexity of medullary thymic epithelial cells (mTEC). While the importance of the medulla for thymus function is clear, the production and maintenance of mTEC diversity remains poorly understood. Here, using ontogenetic and inducible fate-mapping approaches, we identify mTEC-restricted progenitors as a cytokeratin19+ (K19+) TEC subset that emerges in the embryonic thymus. Importantly, labelling of a single cohort of K19+ TEC during embryogenesis sustains the production of multiple mTEC subsets into adulthood, including CCL21+ mTEClo, Aire+ mTEChi and thymic tuft cells. We show K19+ progenitors arise prior to the acquisition of multiple mTEC-defining features including RANK and CCL21 and are generated independently of the key mTEC regulator, Relb. In conclusion, we identify and define a multipotent mTEC progenitor that emerges during embryogenesis to support mTEC diversity into adult life.
    DOI:  https://doi.org/10.1038/s41467-023-37589-4
  6. Nat Methods. 2023 Apr 10.
    Spatiotemporally resolved transcriptomics reveals the subcellular RNA kinetic landscape.
    Jingyi Ren, Haowen Zhou, Hu Zeng, Connie Kangni Wang, Jiahao Huang, Xiaojie Qiu, Xin Sui, Qiang Li, Xunwei Wu, Zuwan Lin, Jennifer A Lo, Kamal Maher, Yichun He, Xin Tang, Judson Lam, Hongyu Chen, Brian Li, David E Fisher, Jia Liu, Xiao Wang.
      Spatiotemporal regulation of the cellular transcriptome is crucial for proper protein expression and cellular function. However, the intricate subcellular dynamics of RNA remain obscured due to the limitations of existing transcriptomics methods. Here, we report TEMPOmap-a method that uncovers subcellular RNA profiles across time and space at the single-cell level. TEMPOmap integrates pulse-chase metabolic labeling with highly multiplexed three-dimensional in situ sequencing to simultaneously profile the age and location of individual RNA molecules. Using TEMPOmap, we constructed the subcellular RNA kinetic landscape in various human cells from transcription and translocation to degradation. Clustering analysis of RNA kinetic parameters across single cells revealed 'kinetic gene clusters' whose expression patterns were shaped by multistep kinetic sculpting. Importantly, these kinetic gene clusters are functionally segregated, suggesting that subcellular RNA kinetics are differentially regulated in a cell-state- and cell-type-dependent manner. Spatiotemporally resolved transcriptomics provides a gateway to uncovering new spatiotemporal gene regulation principles.
    DOI:  https://doi.org/10.1038/s41592-023-01829-8
  7. Nature. 2023 Apr 12.
    Aberrant activation of TCL1A promotes stem cell expansion in clonal haematopoiesis.
    NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium
      Mutations in a diverse set of driver genes increase the fitness of haematopoietic stem cells (HSCs), leading to clonal haematopoiesis1. These lesions are precursors for blood cancers2-6, but the basis of their fitness advantage remains largely unknown, partly owing to a paucity of large cohorts in which the clonal expansion rate has been assessed by longitudinal sampling. Here, to circumvent this limitation, we developed a method to infer the expansion rate from data from a single time point. We applied this method to 5,071 people with clonal haematopoiesis. A genome-wide association study revealed that a common inherited polymorphism in the TCL1A promoter was associated with a slower expansion rate in clonal haematopoiesis overall, but the effect varied by driver gene. Those carrying this protective allele exhibited markedly reduced growth rates or prevalence of clones with driver mutations in TET2, ASXL1, SF3B1 and SRSF2, but this effect was not seen in clones with driver mutations in DNMT3A. TCL1A was not expressed in normal or DNMT3A-mutated HSCs, but the introduction of mutations in TET2 or ASXL1 led to the expression of TCL1A protein and the expansion of HSCs in vitro. The protective allele restricted TCL1A expression and expansion of mutant HSCs, as did experimental knockdown of TCL1A expression. Forced expression of TCL1A promoted the expansion of human HSCs in vitro and mouse HSCs in vivo. Our results indicate that the fitness advantage of several commonly mutated driver genes in clonal haematopoiesis may be mediated by TCL1A activation.
    DOI:  https://doi.org/10.1038/s41586-023-05806-1
  8. Nat Commun. 2023 Apr 10. 14(1): 2004
    Tenascin C+ papillary fibroblasts facilitate neuro-immune interaction in a mouse model of psoriasis.
    Xiaojie Cai, Maoying Han, Fangzhou Lou, Yang Sun, Qianqian Yin, Libo Sun, Zhikai Wang, Xiangxiao Li, Hong Zhou, Zhenyao Xu, Hong Wang, Siyu Deng, Xichen Zheng, Taiyu Zhang, Qun Li, Bin Zhou, Honglin Wang.
      Dermal fibroblasts and cutaneous nerves are important players in skin diseases, while their reciprocal roles during skin inflammation have not been characterized. Here we identify an inflammation-induced subset of papillary fibroblasts that promotes aberrant neurite outgrowth and psoriasiform skin inflammation by secreting the extracellular matrix protein tenascin-C (TNC). Single-cell analysis of fibroblast lineages reveals a Tnc+ papillary fibroblast subset with pro-axonogenesis and neuro-regulation transcriptomic hallmarks. TNC overexpression in fibroblasts boosts neurite outgrowth in co-cultured neurons, while fibroblast-specific TNC ablation suppresses hyperinnervation and alleviates skin inflammation in male mice modeling psoriasis. Dermal γδT cells, the main producers of type 17 pathogenic cytokines, frequently contact nerve fibers in mouse psoriasiform lesions and are likely modulated by postsynaptic signals. Overall, our results highlight the role of an inflammation-responsive fibroblast subset in facilitating neuro-immune synapse formation and suggest potential avenues for future therapeutic research.
    DOI:  https://doi.org/10.1038/s41467-023-37798-x
  9. Nat Biotechnol. 2023 Apr 10.
    The scverse project provides a computational ecosystem for single-cell omics data analysis.
    Scverse Community
      
    DOI:  https://doi.org/10.1038/s41587-023-01733-8
  10. Nat Commun. 2023 Apr 11. 14(1): 2035
    A bacterial autotransporter impairs innate immune responses by targeting the transcription factor TFE3.
    Atri Ta, Rafael Ricci-Azevedo, Swathy O Vasudevan, Skylar S Wright, Puja Kumari, Morena S Havira, Meera Surendran Nair, Vijay A Rathinam, Sivapriya Kailasan Vanaja.
      Type I interferons (IFNs) are consequential cytokines in antibacterial defense. Whether and how bacterial pathogens inhibit innate immune receptor-driven type I IFN expression remains mostly unknown. By screening a library of enterohemorrhagic Escherichia coli (EHEC) mutants, we uncovered EhaF, an uncharacterized protein, as an inhibitor of innate immune responses including IFNs. Further analyses identified EhaF as a secreted autotransporter-a type of bacterial secretion system with no known innate immune-modulatory function-that translocates into host cell cytosol and inhibit IFN response to EHEC. Mechanistically, EhaF interacts with and inhibits the MiT/TFE family transcription factor TFE3 resulting in impaired TANK phosphorylation and consequently, reduced IRF3 activation and type I IFN expression. Notably, EhaF-mediated innate immune suppression promotes EHEC colonization and pathogenesis in vivo. Overall, this study has uncovered a previously unknown autotransporter-based bacterial strategy that targets a specific transcription factor to subvert innate host defense.
    DOI:  https://doi.org/10.1038/s41467-023-37812-2
  11. Proc Natl Acad Sci U S A. 2023 Apr 18. 120(16): e2217864120
    A Cdk5-derived peptide inhibits Cdk5/p25 activity and improves neurodegenerative phenotypes.
    Ping-Chieh Pao, Jinsoo Seo, Audrey Lee, Oleg Kritskiy, Debasis Patnaik, Jay Penney, Ravikiran M Raju, Ute Geigenmuller, M Catarina Silva, Diane E Lucente, James F Gusella, Bradford C Dickerson, Anjanet Loon, Margaret X Yu, Michael Bula, Melody Yu, Stephen J Haggarty, Li-Huei Tsai.
      Aberrant activity of cyclin-dependent kinase (Cdk5) has been implicated in various neurodegenerative diseases. This deleterious effect is mediated by pathological cleavage of the Cdk5 activator p35 into the truncated product p25, leading to prolonged Cdk5 activation and altered substrate specificity. Elevated p25 levels have been reported in humans and rodents with neurodegeneration, and the benefit of genetically blocking p25 production has been demonstrated previously in rodent and human neurodegenerative models. Here, we report a 12-amino-acid-long peptide fragment derived from Cdk5 (Cdk5i) that is considerably smaller than existing peptide inhibitors of Cdk5 (P5 and CIP) but shows high binding affinity toward the Cdk5/p25 complex, disrupts the interaction of Cdk5 with p25, and lowers Cdk5/p25 kinase activity. When tagged with a fluorophore (FITC) and the cell-penetrating transactivator of transcription (TAT) sequence, the Cdk5i-FT peptide exhibits cell- and brain-penetrant properties and confers protection against neurodegenerative phenotypes associated with Cdk5 hyperactivity in cell and mouse models of neurodegeneration, highlighting Cdk5i's therapeutic potential.
    Keywords:  Alzheimer’s disease; Cdk5; neurodegenerative disease; tauopathy
    DOI:  https://doi.org/10.1073/pnas.2217864120
  12. Science. 2023 Apr 14. 380(6641): eabn7113
    The origins and functional effects of postzygotic mutations throughout the human life span.
    Nicole B Rockweiler, Avinash Ramu, Liina Nagirnaja, Wing H Wong, Michiel J Noordam, Casey W Drubin, Ni Huang, Brian Miller, Ellen Z Todres, Katinka A Vigh-Conrad, Antonino Zito, Kerrin S Small, Kristin G Ardlie, Barak A Cohen, Donald F Conrad.
      Postzygotic mutations (PZMs) begin to accrue in the human genome immediately after fertilization, but how and when PZMs affect development and lifetime health remain unclear. To study the origins and functional consequences of PZMs, we generated a multitissue atlas of PZMs spanning 54 tissue and cell types from 948 donors. Nearly half the variation in mutation burden among tissue samples can be explained by measured technical and biological effects, and 9% can be attributed to donor-specific effects. Through phylogenetic reconstruction of PZMs, we found that their type and predicted functional impact vary during prenatal development, across tissues, and through the germ cell life cycle. Thus, methods for interpreting effects across the body and the life span are needed to fully understand the consequences of genetic variants.
    DOI:  https://doi.org/10.1126/science.abn7113
  13. Nat Cell Biol. 2023 Apr 12.
    TBC1D15 drives regeneration of acutely damaged lysosomes.
      
    DOI:  https://doi.org/10.1038/s41556-023-01135-7
  14. Nat Commun. 2023 Apr 12. 14(1): 2071
    Low-dose IL-2 enhances the generation of IL-10-producing immunoregulatory B cells.
    Akimichi Inaba, Zewen Kelvin Tuong, Tian X Zhao, Andrew P Stewart, Rebeccah Mathews, Lucy Truman, Rouchelle Sriranjan, Jane Kennet, Kourosh Saeb-Parsy, Linda Wicker, Frank Waldron-Lynch, Joseph Cheriyan, John A Todd, Ziad Mallat, Menna R Clatworthy.
      Dysfunction of interleukin-10 producing regulatory B cells has been associated with the pathogenesis of autoimmune diseases, but whether regulatory B cells can be therapeutically induced in humans is currently unknown. Here we demonstrate that a subset of activated B cells expresses CD25, and the addition of low-dose recombinant IL-2 to in vitro stimulated peripheral blood and splenic human B cells augments IL-10 secretion. Administration of low dose IL-2, aldesleukin, to patients increases IL-10-producing B cells. Single-cell RNA sequencing of circulating immune cells isolated from low dose IL2-treated patients reveals an increase in plasmablast and plasma cell populations that are enriched for a regulatory B cell gene signature. The transcriptional repressor BACH2 is significantly down-regulated in plasma cells from IL-2-treated patients, BACH2 binds to the IL-10 gene promoter, and Bach2 depletion or genetic deficiency increases B cell IL-10, implicating BACH2 suppression as an important mechanism by which IL-2 may promote an immunoregulatory phenotype in B cells.
    DOI:  https://doi.org/10.1038/s41467-023-37424-w
  15. Nat Genet. 2023 Apr;55(4): 524
    Mutation rates across species.
    Safia Danovi.
      
    DOI:  https://doi.org/10.1038/s41588-023-01381-3
  16. Nat Commun. 2023 Apr 11. 14(1): 2030
    Cryo-EM structures of mitochondrial ABC transporter ABCB10 in apo and biliverdin-bound form.
    Sheng Cao, Yihu Yang, Lili He, Yumo Hang, Xiaodong Yan, Hui Shi, Jiaquan Wu, Zhuqing Ouyang.
      ABCB10, a member of ABC transporter superfamily that locates in the inner membrane of mitochondria, plays crucial roles in hemoglobin synthesis, antioxidative stress and stabilization of the iron transporter mitoferrin-1. Recently, it was found that ABCB10 is a mitochondrial biliverdin exporter. However, the molecular mechanism of biliverdin export by ABCB10 remains elusive. Here we report the cryo-EM structures of ABCB10 in apo (ABCB10-apo) and biliverdin-bound form (ABCB10-BV) at 3.67 Å and 2.85 Å resolution, respectively. ABCB10-apo adopts a wide-open conformation and may thus represent the apo form structure. ABCB10-BV forms a closed conformation and biliverdin situates in a hydrophobic pocket in one protomer and bridges the interaction through hydrogen bonds with the opposing one. We also identify cholesterols sandwiched by BVs and discuss the export dynamics based on these structural and biochemical observations.
    DOI:  https://doi.org/10.1038/s41467-023-37851-9
  17. Nat Commun. 2023 Apr 12. 14(1): 2087
    Expansion of circulating stem-like CD8+ T cells by adding CD122-directed IL-2 complexes to radiation and anti-PD1 therapies in mice.
    Kateryna Onyshchenko, Ren Luo, Elena Guffart, Simone Gaedicke, Anca-Ligia Grosu, Elke Firat, Gabriele Niedermann.
      Combination of radiation therapy (RT) with immune checkpoint blockade can enhance systemic anti-tumor T cell responses. Here, using two mouse tumor models, we demonstrate that adding long-acting CD122-directed IL-2 complexes (IL-2c) to RT/anti-PD1 further increases tumor-specific CD8+ T cell numbers. The highest increase (>50-fold) is found in the blood circulation. Compartmental analysis of exhausted T cell subsets shows that primarily undifferentiated, stem-like, tumor-specific CD8+ T cells expand in the blood; these cells express the chemokine receptor CXCR3, which is required for migration into tumors. In tumor tissue, effector-like but not terminally differentiated exhausted CD8+ T cells increase. Consistent with the surge in tumor-specific CD8+ T cells in blood that are migration and proliferation competent, we observe a CD8-dependent and CXCR3-dependent enhancement of the abscopal effect against distant/non-irradiated tumors and find that CD8+ T cells isolated from blood after RT/anti-PD1/IL-2c triple treatment can be a rich source of tumor-specific T cells for adoptive transfers.
    DOI:  https://doi.org/10.1038/s41467-023-37825-x
  18. Nat Commun. 2023 Apr 08. 14(1): 1994
    Circulating blood eNAMPT drives the circadian rhythms in locomotor activity and energy expenditure.
    Jae Woo Park, Eun Roh, Gil Myoung Kang, So Young Gil, Hyun Kyong Kim, Chan Hee Lee, Won Hee Jang, Se Eun Park, Sang Yun Moon, Seong Jun Kim, So Yeon Jeong, Chae Beom Park, Hyo Sun Lim, Yu Rim Oh, Han Na Jung, Obin Kwon, Byung Soo Youn, Gi Hoon Son, Se Hee Min, Min-Seon Kim.
      Nicotinamide adenine dinucleotide (NAD+) is an essential cofactor of critical enzymes including protein deacetylase sirtuins/SIRTs and its levels in mammalian cells rely on the nicotinamide phosphoribosyltransferase (NAMPT)-mediated salvage pathway. Intracellular NAMPT (iNAMPT) is secreted and found in the blood as extracellular NAMPT (eNAMPT). In the liver, the iNAMPT-NAD+ axis oscillates in a circadian manner and regulates the cellular clockwork. Here we show that the hypothalamic NAD+ levels show a distinct circadian fluctuation with a nocturnal rise in lean mice. This rhythm is in phase with that of plasma eNAMPT levels but not with that of hypothalamic iNAMPT levels. Chemical and genetic blockade of eNAMPT profoundly inhibit the nighttime elevations in hypothalamic NAD+ levels as well as those in locomotor activity (LMA) and energy expenditure (EE). Conversely, elevation of plasma eNAMPT by NAMPT administration increases hypothalamic NAD+ levels and stimulates LMA and EE via the hypothalamic NAD+-SIRT-FOXO1-melanocortin pathway. Notably, obese animals display a markedly blunted circadian oscillation in blood eNAMPT-hypothalamic NAD+-FOXO1 axis as well as LMA and EE. Our findings indicate that the eNAMPT regulation of hypothalamic NAD+ biosynthesis underlies circadian physiology and that this system can be significantly disrupted by obesity.
    DOI:  https://doi.org/10.1038/s41467-023-37517-6
  19. Immunity. 2023 Apr 11. pii: S1074-7613(23)00135-8. [Epub ahead of print]56(4): 687-694
    Modes of type 2 immune response initiation.
    Elizabeth B Kopp, Karen Agaronyan, Ileana Licona-Limón, Simone A Nish, Ruslan Medzhitov.
      Type 2 immunity defends against macro-parasites and can cause allergic diseases. Our understanding of the mechanisms governing the initiation of type 2 immunity is limited, whereas we know more about type 1 immune responses. Type 2 immunity can be triggered by a wide array of inducers that do not share common features and via diverse pathways and mechanisms. To address the complexity of the type 2 initiation pathways, we suggest a framework that conceptualizes different modes of induction of type 2 immunity. We discuss categories of type 2 inducers and their immunogenicity, types of tissue perturbations that are caused by these inducers, sensing strategies for the initiation of Th2 immune responses, and categorization of the signals that are produced in response to type 2 challenges. We describe tissue-specific examples of functional disruption that could lead to type 2 inflammation and propose that different sensing strategies that operate at the tissue level converge on the initiation of type 2 immune responses.
    DOI:  https://doi.org/10.1016/j.immuni.2023.03.015
  20. Proc Natl Acad Sci U S A. 2023 Apr 18. 120(16): e2216811120
    Lipid droplets are intracellular mechanical stressors that impair hepatocyte function.
    Abigail E Loneker, Farid Alisafaei, Aayush Kant, David Li, Paul A Janmey, Vivek B Shenoy, Rebecca G Wells.
      Matrix stiffening and external mechanical stress have been linked to disease and cancer development in multiple tissues, including the liver, where cirrhosis (which increases stiffness markedly) is the major risk factor for hepatocellular carcinoma. Patients with nonalcoholic fatty liver disease and lipid droplet-filled hepatocytes, however, can develop cancer in noncirrhotic, relatively soft tissue. Here, by treating primary human hepatocytes with the monounsaturated fatty acid oleate, we show that lipid droplets are intracellular mechanical stressors with similar effects to tissue stiffening, including nuclear deformation, chromatin condensation, and impaired hepatocyte function. Mathematical modeling of lipid droplets as inclusions that have only mechanical interactions with other cellular components generated results consistent with our experiments. These data show that lipid droplets are intracellular sources of mechanical stress and suggest that nuclear membrane tension integrates cell responses to combined internal and external stresses.
    Keywords:  HNF4α; chromatin condensation; cytoskeleton; mechanobiology; nuclear deformation
    DOI:  https://doi.org/10.1073/pnas.2216811120
  21. Nat Commun. 2023 Apr 10. 14(1): 2020
    Hypoimmune anti-CD19 chimeric antigen receptor T cells provide lasting tumor control in fully immunocompetent allogeneic humanized mice.
    Xiaomeng Hu, Karl Manner, Rowena DeJesus, Kathy White, Corie Gattis, Priscilla Ngo, Christopher Bandoro, Eleonore Tham, Elaine Y Chu, Chi Young, Frank Wells, Ronald Basco, Annabelle Friera, Divy Kangeyan, Pascal Beauchesne, William E Dowdle, Tobias Deuse, Terry J Fry, Aaron E Foster, Sonja Schrepfer.
      Manufacturing autologous chimeric antigen receptor (CAR) T cell therapeutics is complex, and many patients experience treatment delays or cannot be treated at all. Although current allogeneic CAR products have the potential to overcome manufacturing bottlenecks, they are subject to immune rejection and failure to persist in the host, and thus do not provide the same level of efficacy as their autologous counterparts. Here, we aimed to develop universal allogeneic CAR T cells that evade the immune system and produce a durable response. We generated human hypoimmune (HIP) T cells with disrupted B2M, CIITA, and TRAC genes using CRISPR-Cas9 editing. In addition, CD47 and anti-CD19 CAR were expressed using lentiviral transduction. These allogeneic HIP CD19 CAR T cells were compared to allogeneic CD19 CAR T cells that only expressed the anti-CD19 CAR (allo CAR T). In vitro assays for cancer killing and exhaustion revealed no differences between allo CAR T and HIP CAR T cells, confirming that the HIP edits did not negatively affect T cell performance. Clearance of CD19+ tumors by HIP CAR T cells in immunodeficient NSG mice was comparable to that of allo CAR T cells. In fully immunocompetent humanized mice, HIP CAR T cells significantly outperformed allo CAR T cells, showed improved persistence and expansion, and provided lasting cancer clearance. Furthermore, CD47-targeting safety strategies reliably and specifically eliminated HIP CAR T cells. These findings suggest that universal allogeneic HIP CAR T cell-based therapeutics might overcome the limitations associated with poor persistence of allogeneic CAR T cells and exert durable anti-tumor responses.
    DOI:  https://doi.org/10.1038/s41467-023-37785-2
  22. Sci Adv. 2023 Apr 14. 9(15): eabo2467
    Characterization of altered molecular mechanisms in Parkinson's disease through cell type-resolved multiomics analyses.
    Andrew J Lee, Changyoun Kim, Seongwan Park, Jaegeon Joo, Baekgyu Choi, Dongchan Yang, Kyoungho Jun, Junghyun Eom, Seung-Jae Lee, Sun Ju Chung, Robert A Rissman, Jongkyeong Chung, Eliezer Masliah, Inkyung Jung.
      Parkinson's disease (PD) is a progressive neurodegenerative disorder. However, cell type-dependent transcriptional regulatory programs responsible for PD pathogenesis remain elusive. Here, we establish transcriptomic and epigenomic landscapes of the substantia nigra by profiling 113,207 nuclei obtained from healthy controls and patients with PD. Our multiomics data integration provides cell type annotation of 128,724 cis-regulatory elements (cREs) and uncovers cell type-specific dysregulations in cREs with a strong transcriptional influence on genes implicated in PD. The establishment of high-resolution three-dimensional chromatin contact maps identifies 656 target genes of dysregulated cREs and genetic risk loci, uncovering both potential and known PD risk genes. Notably, these candidate genes exhibit modular gene expression patterns with unique molecular signatures in distinct cell types, highlighting altered molecular mechanisms in dopaminergic neurons and glial cells including oligodendrocytes and microglia. Together, our single-cell transcriptome and epigenome reveal cell type-specific disruption in transcriptional regulations related to PD.
    DOI:  https://doi.org/10.1126/sciadv.abo2467
  23. Proc Natl Acad Sci U S A. 2023 Apr 18. 120(16): e2210623120
    A genome-wide optical pooled screen reveals regulators of cellular antiviral responses.
    Rebecca J Carlson, Michael D Leiken, Alina Guna, Nir Hacohen, Paul C Blainey.
      The infection of mammalian cells by viruses and innate immune responses to infection are spatiotemporally organized processes. Cytosolic RNA sensors trigger nuclear translocation of the transcription factor interferon regulatory factor 3 (IRF3) and consequent induction of host immune responses to RNA viruses. Previous genetic screens for factors involved in viral sensing did not resolve changes in the subcellular localization of host or viral proteins. Here, we increased the throughput of our optical pooled screening technology by over fourfold. This allowed us to carry out a genome-wide CRISPR knockout screen using high-resolution multiparameter imaging of cellular responses to Sendai virus infection coupled with in situ cDNA sequencing by synthesis (SBS) to identify 80,408 single guide RNAs (sgRNAs) in 10,366,390 cells-over an order of magnitude more genomic perturbations than demonstrated previously using an in situ SBS readout. By ranking perturbations using human-designed and deep learning image feature scores, we identified regulators of IRF3 translocation, Sendai virus localization, and peroxisomal biogenesis. Among the hits, we found that ATP13A1, an ER-localized P5A-type ATPase, is essential for viral sensing and is required for targeting of mitochondrial antiviral signaling protein (MAVS) to mitochondrial membranes where MAVS must be localized for effective signaling through retinoic acid-inducible gene I (RIG-I). The ability to carry out genome-wide pooled screens with complex high-resolution image-based phenotyping dramatically expands the scope of functional genomics approaches.
    Keywords:  CRISPR screening; IRF3; RIG-I; Sendai; high-content imaging
    DOI:  https://doi.org/10.1073/pnas.2210623120
  24. Cell. 2023 Apr 05. pii: S0092-8674(23)00275-1. [Epub ahead of print]
    Positive selection of somatically mutated clones identifies adaptive pathways in metabolic liver disease.
    Zixi Wang, Shijia Zhu, Yuemeng Jia, Yunguan Wang, Naoto Kubota, Naoto Fujiwara, Ruth Gordillo, Cheryl Lewis, Min Zhu, Tripti Sharma, Lin Li, Qiyu Zeng, Yu-Hsuan Lin, Meng-Hsiung Hsieh, Purva Gopal, Tao Wang, Matt Hoare, Peter Campbell, Yujin Hoshida, Hao Zhu.
      Somatic mutations in nonmalignant tissues accumulate with age and injury, but whether these mutations are adaptive on the cellular or organismal levels is unclear. To interrogate genes in human metabolic disease, we performed lineage tracing in mice harboring somatic mosaicism subjected to nonalcoholic steatohepatitis (NASH). Proof-of-concept studies with mosaic loss of Mboat7, a membrane lipid acyltransferase, showed that increased steatosis accelerated clonal disappearance. Next, we induced pooled mosaicism in 63 known NASH genes, allowing us to trace mutant clones side by side. This in vivo tracing platform, which we coined MOSAICS, selected for mutations that ameliorate lipotoxicity, including mutant genes identified in human NASH. To prioritize new genes, additional screening of 472 candidates identified 23 somatic perturbations that promoted clonal expansion. In validation studies, liver-wide deletion of Tbx3, Bcl6, or Smyd2 resulted in protection against hepatic steatosis. Selection for clonal fitness in mouse and human livers identifies pathways that regulate metabolic disease.
    Keywords:  Gpam; Mboat7; NAFLD; NASH; Smyd2; Tbx3; chronic liver disease; fatty liver disease; in vivo screening; somatic mosaicism
    DOI:  https://doi.org/10.1016/j.cell.2023.03.014
  25. Nat Commun. 2023 Apr 11. 14(1): 2042
    FADS1-arachidonic acid axis enhances arachidonic acid metabolism by altering intestinal microecology in colorectal cancer.
    Chunjie Xu, Lei Gu, Lipeng Hu, Chunhui Jiang, Qing Li, Longci Sun, Hong Zhou, Ye Liu, Hanbing Xue, Jun Li, Zhigang Zhang, Xueli Zhang, Qing Xu.
      Colonocyte metabolism shapes the microbiome. Metabolites are the main mediators of information exchange between intestine and microbial communities. Arachidonic acid (AA) is an essential polyunsaturated fatty acid and its role in colorectal cancer (CRC) remains unexplored. In this study, we show that AA feeding promotes tumor growth in AOM/DSS and intestinal specific Apc-/- mice via modulating the intestinal microecology of increased gram-negative bacteria. Delta-5 desaturase (FADS1), a rate-limiting enzyme, is upregulated in CRC and effectively mediates AA synthesis. Functionally, FADS1 regulates CRC tumor growth via high AA microenvironment-induced enriched gram-negative microbes. Elimination of gram-negative microbe abolishes FADS1 effect. Mechanistically, gram-negative microbes activate TLR4/MYD88 pathway in CRC cells that contributes FADS1-AA axis to metabolize to prostaglandin E2 (PGE2). Cumulatively, we report a potential cancer-promoting mechanism of FADS1-AA axis in CRC that converts raising synthesized AA to PGE2 via modulating the intestinal microecology of gram-negative.
    DOI:  https://doi.org/10.1038/s41467-023-37590-x
  26. Nutr Diabetes. 2023 04 08. 13(1): 4
    Lentinan confers protection against type 1 diabetes by inducing regulatory T cell in spontaneous non-obese diabetic mice.
    Tijun Wu, Zhi Cai, Fandi Niu, Bin Qian, Peng Sun, Nan Yang, Jing Pang, Hongliang Mei, Xiaoai Chang, Fang Chen, Yunxia Zhu, Yating Li, Fu-Gen Wu, Yaqin Zhang, Ting Lei, Xiao Han.
       BACKGROUND: Lentinan (LNT) is a complex fungal component that possesses effective antitumor and immunostimulating properties. However, there is a paucity of studies regarding the effects and mechanisms of LNT on type 1 diabetes.
    OBJECTIVE: In the current study, we investigated whether an intraperitoneal injection of LNT can diminish the risk of developing type 1 diabetes (T1D) in non-obese diabetic (NOD) mice and further examined possible mechanisms of LNT's effects.
    METHODS: Pre-diabetic female NOD mice 8 weeks of age, NOD mice with 140-160 mg/dL, 200-230 mg/dL or 350-450 mg/dL blood glucose levels were randomly divided into two groups and intraperitoneally injected with 5 mg/kg LNT or PBS every other day. Then, blood sugar levels, pancreas slices, spleen, PnLN and pancreas cells from treatment mice were examined.
    RESULTS: Our results demonstrated that low-dosage injections (5 mg/kg) of LNT significantly suppressed immunopathology in mice with autoimmune diabetes but increased the Foxp3+ regulatory T cells (Treg cells) proportion in mice. LNT treatment induced the production of Tregs in the spleen and PnLN cells of NOD mice in vitro. Furthermore, the adoptive transfer of Treg cells extracted from LNT-treated NOD mice confirmed that LNT induced Treg function in vivo and revealed an enhanced suppressive capacity as compared to the Tregs isolated from the control group.
    CONCLUSION: LNT was capable of stimulating the production of Treg cells from naive CD4 + T cells, which implies that LNT exhibits therapeutic values as a tolerogenic adjuvant and may be used to reverse hyperglycaemia in the early and late stages of T1D.
    DOI:  https://doi.org/10.1038/s41387-023-00233-7
  27. Commun Biol. 2023 04 08. 6(1): 381
    Uncovering biology by single-cell proteomics.
    M Shahid Mansuri, Kenneth Williams, Angus C Nairn.
      Recent technological advances have opened the door to single-cell proteomics that can answer key biological questions regarding how protein expression, post-translational modifications, and protein interactions dictate cell state in health and disease.
    DOI:  https://doi.org/10.1038/s42003-023-04635-2
  28. Dev Cell. 2023 Apr 10. pii: S1534-5807(23)00098-9. [Epub ahead of print]58(7): 597-615.e10
    Deregulation of ER-mitochondria contact formation and mitochondrial calcium homeostasis mediated by VDAC in fragile X syndrome.
    Ji Geng, Tejinder Pal Khaket, Jie Pan, Wen Li, Yan Zhang, Yong Ping, Maria Inmaculada Cobos Sillero, Bingwei Lu.
      Loss of fragile X messenger ribonucleoprotein (FMRP) causes fragile X syndrome (FXS), the most prevalent form of inherited intellectual disability. Here, we show that FMRP interacts with the voltage-dependent anion channel (VDAC) to regulate the formation and function of endoplasmic reticulum (ER)-mitochondria contact sites (ERMCSs), structures that are critical for mitochondrial calcium (mito-Ca2+) homeostasis. FMRP-deficient cells feature excessive ERMCS formation and ER-to-mitochondria Ca2+ transfer. Genetic and pharmacological inhibition of VDAC or other ERMCS components restored synaptic structure, function, and plasticity and rescued locomotion and cognitive deficits of the Drosophila dFmr1 mutant. Expressing FMRP C-terminal domain (FMRP-C), which confers FMRP-VDAC interaction, rescued the ERMCS formation and mito-Ca2+ homeostasis defects in FXS patient iPSC-derived neurons and locomotion and cognitive deficits in Fmr1 knockout mice. These results identify altered ERMCS formation and mito-Ca2+ homeostasis as contributors to FXS and offer potential therapeutic targets.
    Keywords:  ER-mitochondria contact site; ERMCS; FMRP; FXS; VDAC; fragile X messenger ribonucleoprotein; fragile X syndrome; mito-Ca(2+) homeostasis; mitochondrial calcium homeostasis; voltage-dependent anion channel
    DOI:  https://doi.org/10.1016/j.devcel.2023.03.002
  29. J Exp Med. 2023 Jul 03. pii: e20221391. [Epub ahead of print]220(7):
    CTLA4 depletes T cell endogenous and trogocytosed B7 ligands via cis-endocytosis.
    Xiaozheng Xu, Preston Dennett, Jibin Zhang, Alice Sherrard, Yunlong Zhao, Takeya Masubuchi, Jack D Bui, Xu Chen, Enfu Hui.
      CD28 and CTLA4 are T cell coreceptors that competitively engage B7 ligands CD80 and CD86 to control adaptive immune responses. While the role of CTLA4 in restraining CD28 costimulatory signaling is well-established, the mechanism has remained unclear. Here, we report that human T cells acquire antigen-presenting-cell (APC)-derived B7 ligands and major histocompatibility complex (MHC) via trogocytosis through CD28:B7 binding. Acquired MHC and B7 enabled T cells to autostimulate, and this process was limited cell-intrinsically by CTLA4, which depletes B7 ligands trogocytosed or endogenously expressed by T cells through cis-endocytosis. Extending this model to the previously proposed extrinsic function of CTLA4 in human regulatory T cells (Treg), we show that blockade of either CD28 or CTLA4 attenuates Treg-mediated depletion of APC B7, indicating that trogocytosis and CTLA4-mediated cis-endocytosis work together to deplete B7 from APCs. Our study establishes CTLA4 as a cell-intrinsic molecular sink that limits B7 availability on the surface of T cells, with implications for CTLA4-targeted therapy.
    DOI:  https://doi.org/10.1084/jem.20221391
  30. Immunity. 2023 Apr 11. pii: S1074-7613(23)00124-3. [Epub ahead of print]56(4): 744-746
    Pathogen metabolite checkpoint: NHR on guard.
    Rejane Rua, Nathalie Pujol.
      How can beneficial microorganisms be distinguished from pathogenic ones? In this issue of Immunity, Peterson et al. discovered that a specific phenazine, which is part of a family of toxic metabolites expressed by pathogenic bacteria, is detected by Caenorhabditis elegans by directly binding to a nuclear hormone receptor, promoting the expression of detoxifying enzymes and immunity-related genes, thus protecting the worm.
    DOI:  https://doi.org/10.1016/j.immuni.2023.03.004
  31. Trends Immunol. 2023 Apr 06. pii: S1471-4906(23)00056-X. [Epub ahead of print]
    Tracking tumor-specific CD8+ T cell responses.
    Kelly P Burke, Samuel C Markson, Arlene H Sharpe.
      In a recent article, Puig-Saus et al. computationally predict and experimentally validate neoantigen-specific T cell responses in patients with melanoma. They identify a restricted set of neoantigens recognized by polyclonal CD8+ T cells as a unique feature of anti-PD-1 responders and engineer autologous tumor-responsive T cells expressing neoantigen-specific TCRs, providing proof-of-concept for future cellular therapies.
    DOI:  https://doi.org/10.1016/j.it.2023.03.012
  32. Nat Commun. 2023 Apr 13. 14(1): 2098
    Previously uncharacterized rectangular bacterial structures in the dolphin mouth.
    Natasha K Dudek, Jesus G Galaz-Montoya, Handuo Shi, Megan Mayer, Cristina Danita, Arianna I Celis, Tobias Viehboeck, Gong-Her Wu, Barry Behr, Silvia Bulgheresi, Kerwyn Casey Huang, Wah Chiu, David A Relman.
      Much remains to be explored regarding the diversity of uncultured, host-associated microbes. Here, we describe rectangular bacterial structures (RBSs) in the mouths of bottlenose dolphins. DNA staining revealed multiple paired bands within RBSs, suggesting the presence of cells dividing along the longitudinal axis. Cryogenic transmission electron microscopy and tomography showed parallel membrane-bound segments that are likely cells, encapsulated by an S-layer-like periodic surface covering. RBSs displayed unusual pilus-like appendages with bundles of threads splayed at the tips. We present multiple lines of evidence, including genomic DNA sequencing of micromanipulated RBSs, 16S rRNA gene sequencing, and fluorescence in situ hybridization, suggesting that RBSs are bacterial and distinct from the genera Simonsiella and Conchiformibius (family Neisseriaceae), with which they share similar morphology and division patterning. Our findings highlight the diversity of novel microbial forms and lifestyles that await characterization using tools complementary to genomics such as microscopy.
    DOI:  https://doi.org/10.1038/s41467-023-37638-y
  33. Immunity. 2023 Apr 11. pii: S1074-7613(23)00136-X. [Epub ahead of print]56(4): 695-703
    Type 2 neuroimmune circuits in the shaping of physiology.
    Roksana M Pirzgalska, Henrique Veiga-Fernandes.
      Type 2 immune responses drive a broad range of biological processes including defense from large parasites, immunity to allergens, and non-immunity-related functions, such as metabolism and tissue homeostasis. The symptoms provoked by type 2 immunity, such as vomiting, coughing or itching, encompass nervous system triggering. Here, we review recent findings that place type 2 neuroimmune circuits at the center stage of immunity at barrier surfaces. We emphasize the homeostatic functions of these circuitries and how deregulation may drive pathology and impact disease outcomes, including in the context of cancer. We discuss a paradigm wherein type 2 neuroimmune circuits are central regulators of organismal physiology.
    DOI:  https://doi.org/10.1016/j.immuni.2023.03.016
  34. Nat Cell Biol. 2023 Apr;25(4): 515
    Specialized septins.
    Daryl J V David.
      
    DOI:  https://doi.org/10.1038/s41556-023-01134-8
  35. Nat Commun. 2023 Apr 12. 14(1): 2068
    Inducible expression of interleukin-12 augments the efficacy of affinity-tuned chimeric antigen receptors in murine solid tumor models.
    Yanping Yang, Huan Yang, Yago Alcaina, Janusz Puc, Alyssa Birt, Yogindra Vedvyas, Michael Gallagher, Srinija Alla, Maria Cristina Riascos, Jaclyn E McCloskey, Karrie Du, Juan Gonzalez-Valdivieso, Irene M Min, Elisa de Stanchina, Matt Britz, Eric von Hofe, Moonsoo M Jin.
      The limited number of targetable tumor-specific antigens and the immunosuppressive nature of the microenvironment within solid malignancies represent major barriers to the success of chimeric antigen receptor (CAR)-T cell therapies. Here, using epithelial cell adhesion molecule (EpCAM) as a model antigen, we used alanine scanning of the complementarity-determining region to fine-tune CAR affinity. This allowed us to identify CARs that could spare primary epithelial cells while still effectively targeting EpCAMhigh tumors. Although affinity-tuned CARs showed suboptimal antitumor activity in vivo, we found that inducible secretion of interleukin-12 (IL-12), under the control of the NFAT promoter, can restore CAR activity to levels close to that of the parental CAR. This strategy was further validated with another affinity-tuned CAR specific for intercellular adhesion molecule-1 (ICAM-1). Only in affinity-tuned CAR-T cells was NFAT activity stringently controlled and restricted to tumors expressing the antigen of interest at high levels. Our study demonstrates the feasibility of specifically gearing CAR-T cells towards recognition of solid tumors by combining inducible IL-12 expression and affinity-tuned CAR.
    DOI:  https://doi.org/10.1038/s41467-023-37646-y
  36. Nat Cell Biol. 2023 Apr;25(4): 515
    Iron regulation in ferroptosis.
    Zhe Wang.
      
    DOI:  https://doi.org/10.1038/s41556-023-01129-5
  37. Nat Commun. 2023 Apr 14. 14(1): 2122
    Priming a vascular-selective cytokine response permits CD8+ T-cell entry into tumors.
    Dae Joong Kim, Swetha Anandh, Jamie L Null, Piotr Przanowski, Sanchita Bhatnagar, Pankaj Kumar, Sarah E Shelton, Erin E Grundy, Katherine B Chiappinelli, Roger D Kamm, David A Barbie, Andrew C Dudley.
      Targeting DNA methyltransferase 1 (DNMT1) has immunomodulatory and anti-neoplastic activity, especially when paired with cancer immunotherapies. Here we explore the immunoregulatory functions of DNMT1 in the tumor vasculature of female mice. Dnmt1 deletion in endothelial cells (ECs) impairs tumor growth while priming expression of cytokine-driven cell adhesion molecules and chemokines important for CD8+ T-cell trafficking across the vasculature; consequently, the efficacy of immune checkpoint blockade (ICB) is enhanced. We find that the proangiogenic factor FGF2 promotes ERK-mediated DNMT1 phosphorylation and nuclear translocation to repress transcription of the chemokines Cxcl9/Cxcl10 in ECs. Targeting Dnmt1 in ECs reduces proliferation but augments Th1 chemokine production and extravasation of CD8+ T-cells, suggesting DNMT1 programs immunologically anergic tumor vasculature. Our study is in good accord with preclinical observations that pharmacologically disrupting DNMT1 enhances the activity of ICB but suggests an epigenetic pathway presumed to be targeted in cancer cells is also operative in the tumor vasculature.
    DOI:  https://doi.org/10.1038/s41467-023-37807-z
  38. Cell Metab. 2023 Apr 04. pii: S1550-4131(23)00091-8. [Epub ahead of print]
    DT-109 ameliorates nonalcoholic steatohepatitis in nonhuman primates.
    Pengxiang Qu, Oren Rom, Ke Li, Linying Jia, Xiaojing Gao, Zhipeng Liu, Shusi Ding, Mingming Zhao, Huiqing Wang, Shuangshuang Chen, Xuelian Xiong, Ying Zhao, Chao Xue, Yang Zhao, Chengshuang Chu, Bo Wen, Alexandra C Finney, Zuowen Zheng, Wenbin Cao, Jinpeng Zhao, Liang Bai, Sihai Zhao, Duxin Sun, Rong Zeng, Jiandie Lin, Wanqing Liu, Lemin Zheng, Jifeng Zhang, Enqi Liu, Y Eugene Chen.
      Nonalcoholic steatohepatitis (NASH) prevalence is rising with no pharmacotherapy approved. A major hurdle in NASH drug development is the poor translatability of preclinical studies to safe/effective clinical outcomes, and recent failures highlight a need to identify new targetable pathways. Dysregulated glycine metabolism has emerged as a causative factor and therapeutic target in NASH. Here, we report that the tripeptide DT-109 (Gly-Gly-Leu) dose-dependently attenuates steatohepatitis and fibrosis in mice. To enhance the probability of successful translation, we developed a nonhuman primate model that histologically and transcriptionally mimics human NASH. Applying a multiomics approach combining transcriptomics, proteomics, metabolomics, and metagenomics, we found that DT-109 reverses hepatic steatosis and prevents fibrosis progression in nonhuman primates, not only by stimulating fatty acid degradation and glutathione formation, as found in mice, but also by modulating microbial bile acid metabolism. Our studies describe a highly translatable NASH model and highlight the need for clinical evaluation of DT-109.
    Keywords:  DT-109; amino acids; bile acids; gut microbiota; nonalcoholic steatohepatitis; nonhuman primates; therapeutic
    DOI:  https://doi.org/10.1016/j.cmet.2023.03.013
  39. Nat Biotechnol. 2023 Apr 13.
    Dandelion uses the single-cell adaptive immune receptor repertoire to explore lymphocyte developmental origins.
    Chenqu Suo, Krzysztof Polanski, Emma Dann, Rik G H Lindeboom, Roser Vilarrasa-Blasi, Roser Vento-Tormo, Muzlifah Haniffa, Kerstin B Meyer, Lisa M Dratva, Zewen Kelvin Tuong, Menna R Clatworthy, Sarah A Teichmann.
      Assessment of single-cell gene expression (single-cell RNA sequencing) and adaptive immune receptor (AIR) sequencing (scVDJ-seq) has been invaluable in studying lymphocyte biology. Here we introduce Dandelion, a computational pipeline for scVDJ-seq analysis. It enables the application of standard V(D)J analysis workflows to single-cell datasets, delivering improved V(D)J contig annotation and the identification of nonproductive and partially spliced contigs. We devised a strategy to create an AIR feature space that can be used for both differential V(D)J usage analysis and pseudotime trajectory inference. The application of Dandelion improved the alignment of human thymic development trajectories of double-positive T cells to mature single-positive CD4/CD8 T cells, generating predictions of factors regulating lineage commitment. Dandelion analysis of other cell compartments provided insights into the origins of human B1 cells and ILC/NK cell development, illustrating the power of our approach. Dandelion is available at https://www.github.com/zktuong/dandelion .
    DOI:  https://doi.org/10.1038/s41587-023-01734-7
  40. Nat Commun. 2023 Apr 13. 14(1): 2099
    High ploidy large cytoplasmic megakaryocytes are hematopoietic stem cells regulators and essential for platelet production.
    Shen Y Heazlewood, Tanveer Ahmad, Benjamin Cao, Huimin Cao, Melanie Domingues, Xuan Sun, Chad K Heazlewood, Songhui Li, Brenda Williams, Madeline Fulton, Jacinta F White, Tom Nebl, Christian M Nefzger, Jose M Polo, Benjamin T Kile, Felix Kraus, Michael T Ryan, Yu B Sun, Peter F M Choong, Sarah L Ellis, Minna-Liisa Anko, Susan K Nilsson.
      Megakaryocytes (MK) generate platelets. Recently, we and others, have reported MK also regulate hematopoietic stem cells (HSC). Here we show high ploidy large cytoplasmic megakaryocytes (LCM) are critical negative regulators of HSC and critical for platelet formation. Using a mouse knockout model (Pf4-Srsf3Δ/Δ) with normal MK numbers, but essentially devoid of LCM, we demonstrate a pronounced increase in BM HSC concurrent with endogenous mobilization and extramedullary hematopoiesis. Severe thrombocytopenia is observed in animals with diminished LCM, although there is no change in MK ploidy distribution, uncoupling endoreduplication and platelet production. When HSC isolated from a microenvironment essentially devoid of LCM reconstitute hematopoiesis in lethally irradiated mice, the absence of LCM increases HSC in BM, blood and spleen, and the recapitulation of thrombocytopenia. In contrast, following a competitive transplant using minimal numbers of WT HSC together with HSC from a microenvironment with diminished LCM, sufficient WT HSC-generated LCM regulates a normal HSC pool and prevents thrombocytopenia. Importantly, LCM are conserved in humans.
    DOI:  https://doi.org/10.1038/s41467-023-37780-7
  41. Nat Commun. 2023 Apr 08. 14(1): 1984
    Trimming the genomic fat: minimising and re-functionalising genomes using synthetic biology.
    Xin Xu, Felix Meier, Benjamin A Blount, Isak S Pretorius, Tom Ellis, Ian T Paulsen, Thomas C Williams.
      Naturally evolved organisms typically have large genomes that enable their survival and growth under various conditions. However, the complexity of genomes often precludes our complete understanding of them, and limits the success of biotechnological designs. In contrast, minimal genomes have reduced complexity and therefore improved engineerability, increased biosynthetic capacity through the removal of unnecessary genetic elements, and less recalcitrance to complete characterisation. Here, we review the past and current genome minimisation and re-functionalisation efforts, with an emphasis on the latest advances facilitated by synthetic genomics, and provide a critical appraisal of their potential for industrial applications.
    DOI:  https://doi.org/10.1038/s41467-023-37748-7
  42. Cell. 2023 Apr 13. pii: S0092-8674(23)00272-6. [Epub ahead of print]186(8): 1532-1534
    The intratumoral microbiota: From microniches to single cells.
    Susan Bullman.
      Solid tumors are composed of a complex and dynamic collection of cell types. Here I discuss the important relationships between cancer cells and bacterial members of the intratumoral microbiota that may provide a fitness advantage within the tumor ecological niche.
    DOI:  https://doi.org/10.1016/j.cell.2023.03.012
  43. Nature. 2023 Apr 12.
    Ageing studies in five animals suggest how to reverse decline.
    Gemma Conroy.
      
    Keywords:  Ageing; Molecular biology; Transcriptomics
    DOI:  https://doi.org/10.1038/d41586-023-01040-x
  44. Nat Commun. 2023 Apr 12. 14(1): 2070
    Inflammatory signals from fatty bone marrow support DNMT3A driven clonal hematopoiesis.
    N Zioni, A Akhiad Bercovich, N Chapal-Ilani, Tal Bacharach, N Rappoport, A Solomon, R Avraham, E Kopitman, Z Porat, M Sacma, G Hartmut, M Scheller, C Muller-Tidow, D Lipka, E Shlush, M Minden, N Kaushansky, Liran I Shlush.
      Both fatty bone marrow (FBM) and somatic mutations in hematopoietic stem cells (HSCs), also termed clonal hematopoiesis (CH) accumulate with human aging. However it remains unclear whether FBM can modify the evolution of CH. To address this question, we herein present the interaction between CH and FBM in two preclinical male mouse models: after sub-lethal irradiation or after castration. An adipogenesis inhibitor (PPARγ inhibitor) is used in both models as a control. A significant increase in self-renewal can be detected in both human and rodent DNMT3AMut-HSCs when exposed to FBM. DNMT3AMut-HSCs derived from older mice interacting with FBM have even higher self-renewal in comparison to DNMT3AMut-HSCs derived from younger mice. Single cell RNA-sequencing on rodent HSCs after exposing them to FBM reveal a 6-10 fold increase in DNMT3AMut-HSCs and an activated inflammatory signaling. Cytokine analysis of BM fluid and BM derived adipocytes grown in vitro demonstrates an increased IL-6 levels under FBM conditions. Anti-IL-6 neutralizing antibodies significantly reduce the selective advantage of DNMT3AMut-HSCs exposed to FBM. Overall, paracrine FBM inflammatory signals promote DNMT3A-driven clonal hematopoiesis, which can be inhibited by blocking the IL-6 pathway.
    DOI:  https://doi.org/10.1038/s41467-023-36906-1
  45. Nat Commun. 2023 Apr 14. 14(1): 2123
    IDH3γ functions as a redox switch regulating mitochondrial energy metabolism and contractility in the heart.
    Maithily S Nanadikar, Ana M Vergel Leon, Jia Guo, Gijsbert J van Belle, Aline Jatho, Elvina S Philip, Astrid F Brandner, Rainer A Böckmann, Runzhu Shi, Anke Zieseniss, Carla M Siemssen, Katja Dettmer, Susanne Brodesser, Marlen Schmidtendorf, Jingyun Lee, Hanzhi Wu, Cristina M Furdui, Sören Brandenburg, Joseph R Burgoyne, Ivan Bogeski, Jan Riemer, Arpita Chowdhury, Peter Rehling, Tobias Bruegmann, Vsevolod V Belousov, Dörthe M Katschinski.
      Redox signaling and cardiac function are tightly linked. However, it is largely unknown which protein targets are affected by hydrogen peroxide (H2O2) in cardiomyocytes that underly impaired inotropic effects during oxidative stress. Here, we combine a chemogenetic mouse model (HyPer-DAO mice) and a redox-proteomics approach to identify redox sensitive proteins. Using the HyPer-DAO mice, we demonstrate that increased endogenous production of H2O2 in cardiomyocytes leads to a reversible impairment of cardiac contractility in vivo. Notably, we identify the γ-subunit of the TCA cycle enzyme isocitrate dehydrogenase (IDH)3 as a redox switch, linking its modification to altered mitochondrial metabolism. Using microsecond molecular dynamics simulations and experiments using cysteine-gene-edited cells reveal that IDH3γ Cys148 and 284 are critically involved in the H2O2-dependent regulation of IDH3 activity. Our findings provide an unexpected mechanism by which mitochondrial metabolism can be modulated through redox signaling processes.
    DOI:  https://doi.org/10.1038/s41467-023-37744-x
  46. Sci Adv. 2023 Apr 14. 9(15): eadf1956
    Defective import of mitochondrial metabolic enzyme elicits ectopic metabolic stress.
    Kazuya Nishio, Tomoyuki Kawarasaki, Yuki Sugiura, Shunsuke Matsumoto, Ayano Konoshima, Yuki Takano, Mayuko Hayashi, Fumihiko Okumura, Takumi Kamura, Tsunehiro Mizushima, Kunio Nakatsukasa.
      Deficiencies in mitochondrial protein import are associated with a number of diseases. However, although nonimported mitochondrial proteins are at great risk of aggregation, it remains largely unclear how their accumulation causes cell dysfunction. Here, we show that nonimported citrate synthase is targeted for proteasomal degradation by the ubiquitin ligase SCFUcc1. Unexpectedly, our structural and genetic analyses revealed that nonimported citrate synthase appears to form an enzymatically active conformation in the cytosol. Its excess accumulation caused ectopic citrate synthesis, which, in turn, led to an imbalance in carbon flux of sugar, a reduction of the pool of amino acids and nucleotides, and a growth defect. Under these conditions, translation repression is induced and acts as a protective mechanism that mitigates the growth defect. We propose that the consequence of mitochondrial import failure is not limited to proteotoxic insults, but that the accumulation of a nonimported metabolic enzyme elicits ectopic metabolic stress.
    DOI:  https://doi.org/10.1126/sciadv.adf1956
  47. Nature. 2023 Apr 12.
    Noncoding translation mitigation.
    Jordan S Kesner, Ziheng Chen, Peiguo Shi, Alexis O Aparicio, Michael R Murphy, Yang Guo, Aditi Trehan, Jessica E Lipponen, Yocelyn Recinos, Natura Myeku, Xuebing Wu.
      Translation is pervasive outside of canonical coding regions, occurring in long noncoding RNAs, canonical untranslated regions and introns1-4, especially in ageing4-6, neurodegeneration5,7 and cancer8-10. Notably, the majority of tumour-specific antigens are results of noncoding translation11-13. Although the resulting polypeptides are often nonfunctional, translation of noncoding regions is nonetheless necessary for the birth of new coding sequences14,15. The mechanisms underlying the surveillance of translation in diverse noncoding regions and how escaped polypeptides evolve new functions remain unclear10,16-19. Functional polypeptides derived from annotated noncoding sequences often localize to membranes20,21. Here we integrate massively parallel analyses of more than 10,000 human genomic sequences and millions of random sequences with genome-wide CRISPR screens, accompanied by in-depth genetic and biochemical characterizations. Our results show that the intrinsic nucleotide bias in the noncoding genome and in the genetic code frequently results in polypeptides with a hydrophobic C-terminal tail, which is captured by the ribosome-associated BAG6 membrane protein triage complex for either proteasomal degradation or membrane targeting. By contrast, canonical proteins have evolved to deplete C-terminal hydrophobic residues. Our results reveal a fail-safe mechanism for the surveillance of unwanted translation from diverse noncoding regions and suggest a possible biochemical route for the preferential membrane localization of newly evolved proteins.
    DOI:  https://doi.org/10.1038/s41586-023-05946-4
  48. Immunity. 2023 Apr 11. pii: S1074-7613(23)00127-9. [Epub ahead of print]56(4): 723-741
    Metabolism in type 2 immune responses.
    Agnieszka M Kabat, Erika L Pearce, Edward J Pearce.
      The immune response is tailored to the environment in which it takes place. Immune cells sense and adapt to changes in their surroundings, and it is now appreciated that in addition to cytokines made by stromal and epithelial cells, metabolic cues provide key adaptation signals. Changes in immune cell activation states are linked to changes in cellular metabolism that support function. Furthermore, metabolites themselves can signal between as well as within cells. Here, we discuss recent progress in our understanding of how metabolic regulation relates to type 2 immunity firstly by considering specifics of metabolism within type 2 immune cells and secondly by stressing how type 2 immune cells are integrated more broadly into the metabolism of the organism as a whole.
    DOI:  https://doi.org/10.1016/j.immuni.2023.03.007
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