bims-nimamd Biomed News
on Neuroimmunity and neuroinflammation in ageing and metabolic disease
Issue of 2022‒06‒26
29 papers selected by
Fawaz Alzaïd
Sorbonne Université

  1. Nat Commun. 2022 Jun 20. 13(1): 3540
      Boosting T cell activation through costimulation directs defense against cancer and viral infections. Despite multiple studies targeting costimulation in clinical trials, the increased potency and reprogramming of T cells endowed by costimulation is poorly understood. Canonical dogma states that transcription mediates T cell activation. Here, we show that the spliceosome, controlling post-transcriptional alternative splicing and alternative polyadenylation, is the most enriched pathway in T cells after CD134/CD137 costimulation. Costimulation of CD8+ T cells significantly increases expression of 29 RNA-binding proteins while RNA-seq uncovers over 1000 differential alternative splicing and polyadenylation events. Using in vivo mouse and in vitro human models, we demonstrate that RNA-binding protein Tardbp is required for effector cytokine production, CD8+ T cell clonal expansion, and isoform regulation after costimulation. The prospect of immune response optimization through reprogramming of mRNA isoform production offered herein opens new avenues for experimentally and therapeutically tuning the activities of T cells.
  2. Nat Immunol. 2022 Jun 20.
      The high mobility group (HMG) transcription factor TCF-1 is essential for early T cell development. Although in vitro biochemical assays suggest that HMG proteins can serve as architectural elements in the assembly of higher-order nuclear organization, the contribution of TCF-1 on the control of three-dimensional (3D) genome structures during T cell development remains unknown. Here, we investigated the role of TCF-1 in 3D genome reconfiguration. Using gain- and loss-of-function experiments, we discovered that the co-occupancy of TCF-1 and the architectural protein CTCF altered the structure of topologically associating domains in T cell progenitors, leading to interactions between previously insulated regulatory elements and target genes at late stages of T cell development. The TCF-1-dependent gain in long-range interactions was linked to deposition of active enhancer mark H3K27ac and recruitment of the cohesin-loading factor NIPBL at active enhancers. These data indicate that TCF-1 has a role in controlling global genome organization during T cell development.
  3. Nat Commun. 2022 Jun 21. 13(1): 3545
      Pancreatic β cell dysfunction contributes to the pathogenesis of type 2 diabetes. MiR-21 has been shown to be induced in the islets of glucose intolerant patients and type 2 diabetic mice. However, the role of miR-21 in the regulation of pancreatic β cell function remains largely elusive. In the current study, we identify the pathway by which miR-21 regulates glucose-stimulated insulin secretion utilizing mice lacking miR-21 in their β cells (miR-21βKO). We find that miR-21βKO mice develop glucose intolerance due to impaired glucose-stimulated insulin secretion. Mechanistic studies reveal that miR-21 enhances glucose uptake and subsequently promotes insulin secretion by up-regulating Glut2 expression in a miR-21-Pdcd4-AP-1 dependent pathway. Over-expression of Glut2 in knockout islets results in rescue of the impaired glucose-stimulated insulin secretion. Furthermore, we demonstrate that delivery of miR-21 into the pancreas of type 2 diabetic db/db male mice is able to promote Glut2 expression and reduce blood glucose level. Taking together, our results reveal that miR-21 in islet β cell promotes insulin secretion and support a role for miR-21 in the regulation of pancreatic β cell function in type 2 diabetes.
  4. Nat Commun. 2022 Jun 20. 13(1): 3525
      Heterochromatin maintains genome integrity and function, and is organised into distinct nuclear domains. Some of these domains are proposed to form by phase separation through the accumulation of HP1ɑ. Mouse heterochromatin contains noncoding major satellite repeats (MSR), which are highly transcribed in mouse embryonic stem cells (ESCs). Here, we report that MSR transcripts can drive the formation of HP1ɑ droplets in vitro, and modulate heterochromatin into dynamic condensates in ESCs, contributing to the formation of large nuclear domains that are characteristic of pluripotent cells. Depleting MSR transcripts causes heterochromatin to transition into a more compact and static state. Unexpectedly, changing heterochromatin's biophysical properties has severe consequences for ESCs, including chromosome instability and mitotic defects. These findings uncover an essential role for MSR transcripts in modulating the organisation and properties of heterochromatin to preserve genome stability. They also provide insights into the processes that could regulate phase separation and the functional consequences of disrupting the properties of heterochromatin condensates.
  5. Nat Commun. 2022 Jun 21. 13(1): 3549
    NHLBI Trans-Omics in Precision Medicine (TOPMed) Consortium
      In a multi-stage analysis of 52,436 individuals aged 17-90 across diverse cohorts and biobanks, we train, test, and evaluate a polygenic risk score (PRS) for hypertension risk and progression. The PRS is trained using genome-wide association studies (GWAS) for systolic, diastolic blood pressure, and hypertension, respectively. For each trait, PRS is selected by optimizing the coefficient of variation (CV) across estimated effect sizes from multiple potential PRS using the same GWAS, after which the 3 trait-specific PRSs are combined via an unweighted sum called "PRSsum", forming the HTN-PRS. The HTN-PRS is associated with both prevalent and incident hypertension at 4-6 years of follow up. This association is further confirmed in age-stratified analysis. In an independent biobank of 40,201 individuals, the HTN-PRS is confirmed to be predictive of increased risk for coronary artery disease, ischemic stroke, type 2 diabetes, and chronic kidney disease.
  6. Nat Commun. 2022 Jun 21. 13(1): 3548
      Despite the fact that proteins carry out nearly all cellular functions and mark the differences of cells, the existing single-cell tools can only analyze dozens of proteins, a scale far from full characterization of cells and tissue yet. Herein, we present a single-cell cyclic multiplex in situ tagging (CycMIST) technology that affords the comprehensive functional proteome profiling of single cells. We demonstrate the technology by detecting 182 proteins that include surface markers, neuron function proteins, neurodegeneration markers, signaling pathway proteins, and transcription factors. Further studies on cells derived from the 5XFAD mice, an Alzheimer's Disease (AD) model, validate the utility of our technology and reveal the deep heterogeneity of brain cells. Through comparison with control mouse cells, we have identified differentially expressed proteins in AD pathology. Our technology could offer new insights into cell machinery and thus may advance many fields including drug discovery, molecular diagnostics, and clinical studies.
  7. Nat Biotechnol. 2022 Jun 20.
      Identification of cancer driver mutations that confer a proliferative advantage is central to understanding cancer; however, searches have often been limited to protein-coding sequences and specific non-coding elements (for example, promoters) because of the challenge of modeling the highly variable somatic mutation rates observed across tumor genomes. Here we present Dig, a method to search for driver elements and mutations anywhere in the genome. We use deep neural networks to map cancer-specific mutation rates genome-wide at kilobase-scale resolution. These estimates are then refined to search for evidence of driver mutations under positive selection throughout the genome by comparing observed to expected mutation counts. We mapped mutation rates for 37 cancer types and applied these maps to identify putative drivers within intronic cryptic splice regions, 5' untranslated regions and infrequently mutated genes. Our high-resolution mutation rate maps, available for web-based exploration, are a resource to enable driver discovery genome-wide.
  8. Cell Stem Cell. 2022 Jun 15. pii: S1934-5909(22)00207-7. [Epub ahead of print]
      Barrier epithelia depend upon resident stem cells for homeostasis, defense, and repair. Epithelial stem cells of small and large intestines (ISCs) respond to their local microenvironments (niches) to fulfill a continuous demand for tissue turnover. The complexity of these niches and underlying communication pathways are not fully known. Here, we report a lymphatic network at the intestinal crypt base that intimately associates with ISCs. Employing in vivo loss of function and lymphatic:organoid cocultures, we show that crypt lymphatics maintain ISCs and inhibit their precocious differentiation. Pairing single-cell and spatial transcriptomics, we apply BayesPrism to deconvolve expression within spatial features and develop SpaceFold to robustly map the niche at high resolution, exposing lymphatics as a central signaling hub for the crypt in general and ISCs in particular. We identify WNT-signaling factors (WNT2, R-SPONDIN-3) and a hitherto unappreciated extracellular matrix protein, REELIN, as crypt lymphatic signals that directly govern the regenerative potential of ISCs.
    Keywords:  REELIN; RSPO3; WNTs; intestinal stem cells; lymphatic:stem cell interactome; lymphatics; organoids; spatial deconvolution; spatial transcriptomics of murine large and small intestine; stem cell niches
  9. Cell. 2022 Jun 23. pii: S0092-8674(22)00658-4. [Epub ahead of print]185(13): 2205-2207
      Interferons are potent antimicrobial effectors and thus an attractive target for pathogen interference. In this issue of Cell, Alphonse et al. reveal that the Shigella effectors OspC1 and OspC3 employ a surprising mechanism to block interferon signaling and attenuate antibacterial responses, thus securing their replicative niche.
  10. Nat Commun. 2022 Jun 20. 13(1): 3518
      System-wide metabolic homeostasis is crucial for maintaining physiological functions of living organisms. Stable-isotope tracing metabolomics allows to unravel metabolic activity quantitatively by measuring the isotopically labeled metabolites, but has been largely restricted by coverage. Delineating system-wide metabolic homeostasis at the whole-organism level remains challenging. Here, we develop a global isotope tracing metabolomics technology to measure labeled metabolites with a metabolome-wide coverage. Using Drosophila as an aging model organism, we probe the in vivo tracing kinetics with quantitative information on labeling patterns, extents and rates on a metabolome-wide scale. We curate a system-wide metabolic network to characterize metabolic homeostasis and disclose a system-wide loss of metabolic coordinations that impacts both intra- and inter-tissue metabolic homeostasis significantly during Drosophila aging. Importantly, we reveal an unappreciated metabolic diversion from glycolysis to serine metabolism and purine metabolism as Drosophila aging. The developed technology facilitates a system-level understanding of metabolic regulation in living organisms.
  11. Nat Metab. 2022 Jun 23.
      Tissue macrophages (Mϕ) are essential effector cells in rheumatoid arthritis (RA), contributing to autoimmune tissue inflammation through diverse effector functions. Their arthritogenic potential depends on their proficiency to survive in the glucose-depleted environment of the inflamed joint. Here, we identify a mechanism that links metabolic adaptation to nutrient stress with the efficacy of tissue Mϕ to activate adaptive immunity by presenting antigen to tissue-invading T cells. Specifically, Mϕ populating the rheumatoid joint produce and respond to the small cytokine CCL18, which protects against cell death induced by glucose withdrawal. Mechanistically, CCL18 induces the transcription factor RFX5 that selectively upregulates glutamate dehydrogenase 1 (GLUD1), thus enabling glutamate utilization to support energy production. In parallel, RFX5 enhances surface expression of HLA-DR molecules, promoting Mϕ-dependent expansion of antigen-specific T cells. These data place CCL18 at the top of a RFX5-GLUD1 survival pathway and couple adaptability to nutrient conditions in the tissue environment to antigen-presenting function in autoimmune tissue inflammation.
  12. Cell. 2022 Jun 23. pii: S0092-8674(22)00698-5. [Epub ahead of print]185(13): 2201-2203
      The ε4 variant in the APOE gene is the strongest genetic risk factor for Alzheimer's disease. How does this gene impact different cell types in the brain to increase disease risk? In this issue of Cell, TCW and colleagues report APOE-driven cell-type-specific changes that may contribute to Alzheimer's disease risk.
  13. Nat Commun. 2022 Jun 22. 13(1): 3560
      Methicillin-resistant Staphylococcus aureus (MRSA) is a bacterial pathogen responsible for significant human morbidity and mortality. Post-transcriptional regulation by small RNAs (sRNAs) has emerged as an important mechanism for controlling virulence. However, the functionality of the majority of sRNAs during infection is unknown. To address this, we performed UV cross-linking, ligation, and sequencing of hybrids (CLASH) in MRSA to identify sRNA-RNA interactions under conditions that mimic the host environment. Using a double-stranded endoribonuclease III as bait, we uncovered hundreds of novel sRNA-RNA pairs. Strikingly, our results suggest that the production of small membrane-permeabilizing toxins is under extensive sRNA-mediated regulation and that their expression is intimately connected to metabolism. Additionally, we also uncover an sRNA sponging interaction between RsaE and RsaI. Taken together, we present a comprehensive analysis of sRNA-target interactions in MRSA and provide details on how these contribute to the control of virulence in response to changes in metabolism.
  14. Nat Commun. 2022 Jun 20. 13(1): 3538
      In the era of single-cell sequencing, there is a growing need to extract insights from data with clustering methods. Here, we introduce Forest Fire Clustering, an efficient and interpretable method for cell-type discovery from single-cell data. Forest Fire Clustering makes minimal prior assumptions and, different from current approaches, calculates a non-parametric posterior probability that each cell is assigned a cell-type label. These posterior distributions allow for the evaluation of a label confidence for each cell and enable the computation of "label entropies", highlighting transitions along developmental trajectories. Furthermore, we show that Forest Fire Clustering can make robust, inductive inferences in an online-learning context and can readily scale to millions of cells. Finally, we demonstrate that our method outperforms state-of-the-art clustering approaches on diverse benchmarks of simulated and experimental data. Overall, Forest Fire Clustering is a useful tool for rare cell type discovery in large-scale single-cell analysis.
  15. Nat Commun. 2022 Jun 21. 13(1): 3544
      Immunometabolism contributes to inflammation, but how activated macrophages acquire extracellular nutrients to fuel inflammation is largely unknown. Here, we show that the plasma membrane potential (Vm) of macrophages mediated by Kir2.1, an inwardly-rectifying K+ channel, is an important determinant of nutrient acquisition and subsequent metabolic reprogramming promoting inflammation. In the absence of Kir2.1 activity, depolarized macrophage Vm lead to a caloric restriction state by limiting nutrient uptake and concomitant adaptations in nutrient conservation inducing autophagy, AMPK (Adenosine 5'-monophosphate-activated protein kinase), and GCN2 (General control nonderepressible 2), which subsequently depletes epigenetic substrates feeding histone methylation at loci of a cluster of metabolism-responsive inflammatory genes, thereby suppressing their transcription. Kir2.1-mediated Vm supports nutrient uptake by facilitating cell-surface retention of nutrient transporters such as 4F2hc and GLUT1 by its modulation of plasma membrane phospholipid dynamics. Pharmacological targeting of Kir2.1 alleviated inflammation triggered by LPS or bacterial infection in a sepsis model and sterile inflammation in human samples. These findings identify an ionic control of macrophage activation and advance our understanding of the immunomodulatory properties of Vm that links nutrient inputs to inflammatory diseases.
  16. Nat Commun. 2022 Jun 23. 13(1): 3585
      Mitochondrial ADP/ATP carriers import ADP into the mitochondrial matrix and export ATP to the cytosol to fuel cellular processes. Structures of the inhibited cytoplasmic- and matrix-open states have confirmed an alternating access transport mechanism, but the molecular details of substrate binding remain unresolved. Here, we evaluate the role of the solvent-exposed residues of the translocation pathway in the process of substrate binding. We identify the main binding site, comprising three positively charged and a set of aliphatic and aromatic residues, which bind ADP and ATP in both states. Additionally, there are two pairs of asparagine/arginine residues on opposite sides of this site that are involved in substrate binding in a state-dependent manner. Thus, the substrates are directed through a series of binding poses, inducing the conformational changes of the carrier that lead to their translocation. The properties of this site explain the electrogenic and reversible nature of adenine nucleotide transport.
  17. Front Immunol. 2022 ;13 879648
      Background: Decoy receptor 3 (DcR3) belongs to the tumor necrosis factor (TNF) receptor superfamily and neutralizes TNF ligands, including FasL and TRAIL, to prevent T activation during T-cell priming. However, the cellular mechanisms underlying acute cell-mediated rejection (ACMR) remain unknown.Methods: We generated DcR3 transgenic (Tg) mice and mice with high DcR3 expression (HDE) to study both in vivo and in vitro. FasR RNA knockdown in immortalized CD4+CD8+ T-cells was used to survey the role of DcR3 on FasR/Fas-associated protein with death domain (FADD)/caspase 8 pathway and its cross-link to TNF receptor-associated factor 1 (TNFR1)-associated death domain protein (TRADD) in suppressing TNFR1. TNF/TRADD knockout mice were used to show the importance of TNF adaptor protein.
    Results: DcR3.Fc suppressed C57BL/6 female T-cell activation and transformation into CD4+CD69+, CD4+CD44+, and CD4+CD25+Foxp3+ when compared with isotype IgG1 and its co-treatment with FasL/TRAIL after exposing to bone marrow-derived dendritic cells (BMDCs) that carried alloantigen with male H-Y and minor antigenic determinant. Interleukin-17 and interferon-γ productions by BMDC-activated T-cells were lowered after co-treating with DcR3.Fc. DcR3.Fc induced effector T-cells (Teffs) and was susceptible to FasR-mediated apoptosis through the FADD/TRADD/caspase 8 pathway. After exposing to DcR3.Fc, TRADD was silenced, likely turning down the inflammatory response. The systemic effects of DcR3 Tg mice and HDE phenotype induced by the promoter of cytomegalovirus not only attenuated ACMR severity but also ameliorated the high serum creatinine and blood urea nitrogen levels even with high T-cell exposure frequencies. Besides this, DcR3 has minor biological effects on both MHC-matched and MHC-mismatched models.
    Conclusions: High DcR3 doses protect renal tubular epithelial cells from acute T-cell attack during the T-cell priming stage via interfering with TNF ligand-mediated reverse signaling and possibly promoting Teff apoptosis through FasR upregulation. Our findings supported that the decoy receptor is involved in T-cell modulation in kidney transplant rejection.
    Keywords:  adaptor protein; decoy receptor; knockout; minor antigenic determinant; phenotype; transgenic mice
  18. Cell Rep. 2022 Jun 21. pii: S2211-1247(22)00760-4. [Epub ahead of print]39(12): 110974
      Severity of pulmonary viral infections, including influenza A virus (IAV), is linked to excessive immunopathology, which impairs lung function. Thus, the same immune responses that limit viral replication can concomitantly cause lung damage that must be countered by largely uncharacterized disease tolerance mechanisms. Here, we show that mitochondrial cyclophilin D (CypD) protects against IAV via disease tolerance. CypD-/- mice are significantly more susceptible to IAV infection despite comparable antiviral immunity. This susceptibility results from damage to the lung epithelial barrier caused by a reduction in interleukin-22 (IL-22)-producing natural killer (NK) cells. Transcriptomic and functional data reveal that CypD-/- NK cells are immature and have altered cellular metabolism and impaired IL-22 production, correlating with dysregulated bone marrow lymphopoiesis. Administration of recombinant IL-22 or transfer of wild-type (WT) NK cells abrogates pulmonary damage and protects CypD-/- mice after IAV infection. Collectively, these results demonstrate a key role for CypD in NK cell-mediated disease tolerance.
    Keywords:  CP: Immunology; CP: Microbiology; IL-22; NK cells; cyclophilin D; disease tolerance; influenza; lymphopoiesis
  19. Diabetes. 2022 Jun 22. pii: db210989. [Epub ahead of print]
      Inflammation and oxidative stress in pancreatic islets amplify the appearance of various post-translational modifications (PTMs) to self-proteins. Herein, we identified a select group of carbonylated islet proteins arising before the onset of hyperglycemia in non-obese diabetic mice. Of interest, we identified carbonyl modification of the prolyl-4-hydroxylase beta subunit (P4Hb) that is responsible for proinsulin folding and trafficking as an autoantigen in both human and murine type 1 diabetes. We found the carbonylated P4Hb is amplified in stressed islets coincident with decreased glucose-stimulated insulin secretion and altered proinsulin to insulin ratios. Autoantibodies against P4Hb were detected in prediabetic NOD mice and in early human type 1 diabetes prior to the onset of anti-insulin autoimmunity. Moreover, we identify autoreactive CD4+ T cell responses toward carbonyl-P4Hb epitopes in the circulation of patients with type 1 diabetes. Our studies provide mechanistic insight into the pathways of proinsulin metabolism and in creating autoantigenic forms of insulin in type 1 diabetes.
  20. Nat Commun. 2022 Jun 23. 13(1): 3605
      The cell-type-specific recording and manipulation is instrumental to disentangle causal neural mechanisms in physiology and behavior and increasingly requires intersectional control; however, current approaches are largely limited by the number of intersectional features, incompatibility of common effectors and insufficient gene expression. Here, we utilized the protein-splicing technique mediated by intervening sequences (intein) and devised an intein-based intersectional synthesis of transactivator (IBIST) to selectively control gene expression of common effectors in multiple-feature defined cell types in mice. We validated the specificity and sufficiency of IBIST to control fluorophores, optogenetic opsins and Ca2+ indicators in various intersectional conditions. The IBIST-based Ca2+ imaging showed that the IBIST can intersect five features and that hippocampal neurons tune differently to distinct emotional stimuli depending on the pattern of projection targets. Collectively, the IBIST multiplexes the capability to intersect cell-type features and controls common effectors to effectively regulate gene expression, monitor and manipulate neural activities.
  21. Nat Commun. 2022 Jun 18. 13(1): 3512
      Prime editing enables search-and-replace genome editing but is limited by low editing efficiency. We present a high-throughput approach, the Peptide Self-Editing sequencing assay (PepSEq), to measure how fusion of 12,000 85-amino acid peptides influences prime editing efficiency. We show that peptide fusion can enhance prime editing, prime-enhancing peptides combine productively, and a top dual peptide-prime editor increases prime editing significantly in multiple cell lines across dozens of target sites. Top prime-enhancing peptides function by increasing translation efficiency and serve as broadly useful tools to improve prime editing efficiency.
  22. Sci Immunol. 2022 Jun 24. 7(72): eabo5407
      Differing from the mouse Foxp3 gene that encodes only one protein product, human FOXP3 encodes two major isoforms through alternative splicing-a longer isoform (FOXP3 FL) containing all the coding exons and a shorter isoform lacking the amino acids encoded by exon 2 (FOXP3 ΔE2). The two isoforms are naturally expressed in humans, yet their differences in controlling regulatory T cell phenotype and functionality remain unclear. In this study, we show that patients expressing only the shorter isoform fail to maintain self-tolerance and develop immunodeficiency, polyendocrinopathy, and enteropathy X-linked (IPEX) syndrome. Mice with Foxp3 exon 2 deletion have excessive follicular helper T (TFH) and germinal center B (GC B) cell responses, and develop systemic autoimmune disease with anti-dsDNA and antinuclear autoantibody production, as well as immune complex glomerulonephritis. Despite having normal suppressive function in in vitro assays, regulatory T cells expressing FOXP3 ΔE2 are unstable and sufficient to induce autoimmunity when transferred into Tcrb-deficient mice. Mechanistically, the FOXP3 ΔE2 isoform allows increased expression of selected cytokines, but decreased expression of a set of positive regulators of Foxp3 without altered binding to these gene loci. These findings uncover indispensable functions of the FOXP3 exon 2 region, highlighting a role in regulating a transcriptional program that maintains Treg stability and immune homeostasis.
  23. Elife. 2022 Jun 22. pii: e75580. [Epub ahead of print]11
      Endoplasmic reticulum (ER) to nucleus homeostatic signaling, known as the unfolded protein response (UPR), relies on the non-canonical splicing of XBP1 mRNA. The molecular switch that initiates splicing is the oligomerization of the ER stress sensor and UPR endonuclease IRE1α (inositol-requiring enzyme 1 alpha). While IRE1α can form large clusters that have been proposed to function as XBP1 processing centers on the ER, the actual oligomeric state of active IRE1α complexes as well as the targeting mechanism that recruits XBP1 to IRE1α oligomers remains unknown. Here, we have developed a single-molecule imaging approach to monitor the recruitment of individual XBP1 transcripts to the ER surface. Using this methodology, we confirmed that stable ER association of unspliced XBP1 mRNA is established through HR2 (hydrophobic region 2)-dependent targeting and relies on active translation. In addition, we show that IRE1α-catalyzed splicing mobilizes XBP1 mRNA from the ER membrane in response to ER stress. Surprisingly, we find that XBP1 transcripts are not recruited into large IRE1α clusters, which are only observed upon overexpression of fluorescently tagged IRE1α during ER stress. Our findings support a model where ribosome-engaged, immobilized XBP1 mRNA is processed by small IRE1α assemblies that could be dynamically recruited for processing of mRNA transcripts on the ER.
    Keywords:  ER; IRE1; XBP1; cell biology; human; imaging; single-molecule; unfolded protein response
  24. Nat Commun. 2022 Jun 23. 13(1): 3591
      In 1948, Angus Bateman presented experiments and concepts that remain influential and debated in sexual selection. The Bateman gradient relates reproductive success to mate number, and Bateman presented this as the cause of intra-masculine selection. A deeper causal level was subsequently asserted: that the ultimate cause of sex differences in Bateman gradients is the sex difference in gamete numbers, an argument that remains controversial and without mathematical backup. Here I develop models showing how asymmetry in gamete numbers alone can generate steeper Bateman gradients in males. This conclusion remains when the further asymmetry of internal fertilisation is added to the model and fertilisation is efficient. Strong gamete limitation can push Bateman gradients towards equality under external fertilisation and reverse them under internal fertilisation. Thus, this study provides a mathematical formalisation of Bateman's brief verbal claim, while demonstrating that the link between gamete number and Bateman gradients is not inevitable nor trivial.
  25. J Immunol. 2022 Jun 20. pii: ji2101014. [Epub ahead of print]
      TCR ligation with an Ag presented on MHC molecules promotes T cell activation, leading to the selection, differentiation, and proliferation of T cells and cytokine production. These immunological events are optimally arranged to provide appropriate responses against a variety of pathogens. We here propose signal-transducing adaptor protein-2 (STAP-2) as a new positive regulator of TCR signaling. STAP-2-deficient T cells showed reduced, whereas STAP-2-overexpressing T cells showed enhanced, TCR-mediated signaling and downstream IL-2 production. For the mechanisms, STAP-2 associated with TCR-proximal CD3ζ immunoreceptor tyrosine activation motifs and phosphorylated LCK, resulting in enhancement of their binding after TCR stimulation. In parallel, STAP-2 expression is required for full activation of downstream TCR signaling. Importantly, STAP-2-deficient mice exhibited slight phenotypes of CD4+ T-cell-mediated inflammatory diseases, such as experimental autoimmune encephalomyelitis, whereas STAP-2-overexpressing transgenic mice showed severe phenotypes of these diseases. Together, STAP-2 is an adaptor protein to enhance TCR signaling; therefore, manipulating STAP-2 will have an ability to improve the treatment of patients with autoimmune diseases as well as the chimeric Ag receptor T cell therapy.
  26. Commun Biol. 2022 Jun 23. 5(1): 620
      Imbalanced mitochondrial dNTP pools are known players in the pathogenesis of multiple human diseases. Here we show that, even under physiological conditions, dGTP is largely overrepresented among other dNTPs in mitochondria of mouse tissues and human cultured cells. In addition, a vast majority of mitochondrial dGTP is tightly bound to NDUFA10, an accessory subunit of complex I of the mitochondrial respiratory chain. NDUFA10 shares a deoxyribonucleoside kinase (dNK) domain with deoxyribonucleoside kinases in the nucleotide salvage pathway, though no specific function beyond stabilizing the complex I holoenzyme has been described for this subunit. We mutated the dNK domain of NDUFA10 in human HEK-293T cells while preserving complex I assembly and activity. The NDUFA10E160A/R161A shows reduced dGTP binding capacity in vitro and leads to a 50% reduction in mitochondrial dGTP content, proving that most dGTP is directly bound to the dNK domain of NDUFA10. This interaction may represent a hitherto unknown mechanism regulating mitochondrial dNTP availability and linking oxidative metabolism to DNA maintenance.
  27. FASEB J. 2022 May;36 Suppl 1
      BACKGROUND: Alcohol-related liver disease (ALD) is a worldwide health problem without successful treatment. Aging is associate with obesity, which are known a risk factor that aggravate ALD. We and others have previously demonstrated that chronic plus binge alcohol increases adipose tissue lipolysis and promotes alcohol-induced liver injury through the adipose-liver crosstalk. In the present study, we investigated the role of autophagy receptor protein SQSTM1/p62 in adipose-liver crosstalk and the effects of aging and obesity in ALD.METHODS: Whole-body p62 knockout (KO) and their matched wild type young (2-3 months) and aged (13-15 months) mice were subjected to chronic plus binge (Gao-binge) alcohol model.  Adipose and liver tissues were collected for biochemical and histological analysis.
    RESULTS: p62 KO mice developed mature-onset obesity in aged mice with increased both white and brown adipose tissue mass. Gao-binge alcohol feeding decreased both the white and adipose mass regardless of the age and genotypes of mice. Alcohol feeding increased levels of serum free fatty acids regardless of the genotypes of the mice although the serum levels of glycerol only significantly increased in alcohol fed aged p62 KO mice. Alcohol feeding increased levels of serum ALT and hepatic triglyceride (TG) in both young and aged WT and p62 KO mice, but no significant differences were found among the young WT and p62 KO mice as well as aged WT vs young WT mice. However, alcohol-fed aged p62 KO mice had significantly higher levels of serum ALT and hepatic TG as well as fibrosis and inflammation markers than alcohol-fed aged WT mice. Mechanistically, aged p62 KO mice had increased de novo lipogenesis and senescence with increased senescence associated secretory phenotype with similar increased oxidative stress compared with matched WT mice.
    CONCLUSION: We established a genetic obesity/metabolic syndrome mouse model with alcohol consumption. Loss of p62 in aged mice leads to obesity with metabolic syndrome that exacerbates alcohol-induced liver injury via increased de novo lipogenesis and senescence.
  28. Nature. 2022 Jun 22.
      The identification of mechanisms to promote memory T (Tmem) cells has important implications for vaccination and anti-cancer immunotherapy1-4. Using a CRISPR-based screen for negative regulators of Tmem cell generation in vivo5, here we identify multiple components of the mammalian canonical BRG1/BRM-associated factor (cBAF)6,7. Several components of the cBAF complex are essential for the differentiation of activated CD8+ T cells into T effector (Teff) cells, and their loss promotes Tmem cell formation in vivo. During the first division of activated CD8+ T cells, cBAF and MYC8 frequently co-assort asymmetrically to the two daughter cells. Daughter cells with high MYC and high cBAF display a cell fate trajectory towards Teff cells, whereas those with low MYC and low cBAF preferentially differentiate towards Tmem cells. The cBAF complex and MYC physically interact to establish the chromatin landscape in activated CD8+ T cells. Treatment of naive CD8+ T cells with a putative cBAF inhibitor during the first 48 h of activation, before the generation of chimeric antigen receptor T (CAR-T) cells, markedly improves efficacy in a mouse solid tumour model. Our results establish cBAF as a negative determinant of Tmem cell fate and suggest that manipulation of cBAF early in T cell differentiation can improve cancer immunotherapy.