bims-nimamd Biomed News
on Neuroimmunity and neuroinflammation in ageing and metabolic disease
Issue of 2024‒02‒18
fifty-nine papers selected by
Fawaz Alzaïd, Sorbonne Université
  1. Fudging the volcano-plot without dredging the data.
  2. Exams with empathy.
  3. Epiallelic variation of non-coding RNA genes and their phenotypic consequences.
  4. Smoking scars the immune system for years after quitting.
  5. Tackling biases in clinical trials to ensure diverse representation and effective outcomes.
  6. EFHD2 suppresses intestinal inflammation by blocking intestinal epithelial cell TNFR1 internalization and cell death.
  7. Reduced progranulin increases tau and α-synuclein inclusions and alters mouse tauopathy phenotypes via glucocerebrosidase.
  8. TYK2 signaling promotes the development of autoreactive CD8+ cytotoxic T lymphocytes and type 1 diabetes.
  9. Regulation goes awry in the liver.
  10. Neutrophils become pro-angiogenic in tumours.
  11. Distinct ontogenetic lineages dictate cDC2 heterogeneity.
  12. Sonic hedgehog-heat shock protein 90β axis promotes the development of nonalcoholic steatohepatitis in mice.
  13. Decoding the autoantibody reactome.
  14. Home exergame prevents falls.
  15. HIV cure: The daunting scale of the problem.
  16. Genetic determinants of micronucleus formation in vivo.
  17. A spotlight on the tuberculosis epidemic in South Africa.
  18. Lineage motifs as developmental modules for control of cell type proportions.
  19. Human ILC2s can act as cytolytic killers.
  20. The HRI branch of the integrated stress response selectively triggers mitophagy.
  21. Pro-ferroptotic signaling promotes arterial aging via vascular smooth muscle cell senescence.
  22. In situ structure of actin remodeling during glucose-stimulated insulin secretion using cryo-electron tomography.
  23. Hunger guides immunity to friend versus foe.
  24. Telomerase misbehaves after a breakup.
  25. Autonomous transposons tune their sequences to ensure somatic suppression.
  26. HKDC1 promotes tumor immune evasion in hepatocellular carcinoma by coupling cytoskeleton to STAT1 activation and PD-L1 expression.
  27. PD-1 and CTLA-4 blockade promote CD86-driven Treg responses upon radiotherapy of lymphocyte-depleted cancer in mice.
  28. A system for inducible mitochondria-specific protein degradation in vivo.
  29. Adipocyte p53 coordinates the response to intermittent fasting by regulating adipose tissue immune cell landscape.
  30. Order and disorder in clathrin-mediated endocytosis.
  31. Complement in maternal milk shapes the infant microbiome.
  32. A hepatic network of dendritic cells mediates CD4 T cell help outside lymphoid organs.
  33. Who goes there?
  34. Heterogeneity of hepatocyte dynamics restores liver architecture after chemical, physical or viral damage.
  35. Sequential stacking link prediction algorithms for temporal networks.
  36. Blood protein markers predict 15-year risk of dementia.
  37. Reactivating antitumor immunity by inhibiting JMJD1C.
  38. The HIF transcription network exerts innate antiviral activity in neurons and limits brain inflammation.
  39. Early dementia diagnosis: blood proteins reveal at-risk people.
  40. Persistence of backtracking by human RNA polymerase II.
  41. Cell softness renders cytotoxic T lymphocytes and T leukemic cells resistant to perforin-mediated killing.
  42. Immunodeficiency disease linked to cell senescence.
  43. Cryo-EM structures of lipidic fibrils of amyloid-β (1-40).
  44. Innate and adaptive immune cell interaction drives inflammasome activation and hepatocyte apoptosis in murine liver injury from immune checkpoint inhibitors.
  45. Move over, CRISPR: RNA-editing therapies pick up steam.
  46. TGF-β blockade drives a transitional effector phenotype in T cells reversing SIV latency and decreasing SIV reservoirs in vivo.
  47. Chromatin attachment to the nuclear matrix represses hypocotyl elongation in Arabidopsis thaliana.
  48. Suppression of IL-1β promotes beneficial accumulation of fibroblast-like cells in atherosclerotic plaques in clonal hematopoiesis.
  49. Validation of biomarkers of aging.
  50. Orchestration of the Adipose Tissue Immune Landscape by Adipocytes.
  51. TISSUE: uncertainty-calibrated prediction of single-cell spatial transcriptomics improves downstream analyses.
  52. Single-nucleoid architecture reveals heterogeneous packaging of mitochondrial DNA.
  53. Selenium abandons selenoproteins to inhibit ferroptosis rapidly.
  54. Methyltransferase Setd2 prevents T cell-mediated autoimmune diseases via phospholipid remodeling.
  55. Linking host genetics to gut microbial variation.
  56. Structure of human phagocyte NADPH oxidase in the activated state.
  57. Eco-evolutionary dynamics of gut phageome in wild gibbons (Hoolock tianxing) with seasonal diet variations.
  58. A GPCR-neuropeptide axis dampens hyperactive neutrophils by promoting an alternative-like polarization during bacterial infection.
  59. Structural role for DNA Ligase IV in promoting the fidelity of non-homologous end joining.
  1. Nat Commun. 2024 Feb 15. 15(1): 1392
    Fudging the volcano-plot without dredging the data.
    Thomas Burger.
      
    DOI:  https://doi.org/10.1038/s41467-024-45834-7
  2. Science. 2024 Feb 16. 383(6684): 790
    Exams with empathy.
    Jan Philipp Röer.
      
    DOI:  https://doi.org/10.1126/science.ado5972
  3. Nat Commun. 2024 Feb 14. 15(1): 1375
    Epiallelic variation of non-coding RNA genes and their phenotypic consequences.
    Jie Liu, Xuehua Zhong.
      Epigenetic variations contribute greatly to the phenotypic plasticity and diversity. Current functional studies on epialleles have predominantly focused on protein-coding genes, leaving the epialleles of non-coding RNA (ncRNA) genes largely understudied. Here, we uncover abundant DNA methylation variations of ncRNA genes and their significant correlations with plant adaptation among 1001 natural Arabidopsis accessions. Through genome-wide association study (GWAS), we identify large numbers of methylation QTL (methylQTL) that are independent of known DNA methyltransferases and enriched in specific chromatin states. Proximal methylQTL closely located to ncRNA genes have a larger effect on DNA methylation than distal methylQTL. We ectopically tether a DNA methyltransferase MQ1v to miR157a by CRISPR-dCas9 and show de novo establishment of DNA methylation accompanied with decreased miR157a abundance and early flowering. These findings provide important insights into the genetic basis of epigenetic variations and highlight the contribution of epigenetic variations of ncRNA genes to plant phenotypes and diversity.
    DOI:  https://doi.org/10.1038/s41467-024-45771-5
  4. Nature. 2024 Feb 14.
    Smoking scars the immune system for years after quitting.
    Heidi Ledford.
      
    Keywords:  Diseases; Immunology; Obesity; Public health; Virology
    DOI:  https://doi.org/10.1038/d41586-024-00412-1
  5. Nat Commun. 2024 Feb 15. 15(1): 1407
    Tackling biases in clinical trials to ensure diverse representation and effective outcomes.
      
    DOI:  https://doi.org/10.1038/s41467-024-45718-w
  6. Nat Commun. 2024 Feb 12. 15(1): 1282
    EFHD2 suppresses intestinal inflammation by blocking intestinal epithelial cell TNFR1 internalization and cell death.
    Jiacheng Wu, Xiaoqing Xu, Jiaqi Duan, Yangyang Chai, Jiaying Song, Dongsheng Gong, Bingjing Wang, Ye Hu, Taotao Han, Yuanyuan Ding, Yin Liu, Jingnan Li, Xuetao Cao.
      TNF acts as one pathogenic driver for inducing intestinal epithelial cell (IEC) death and substantial intestinal inflammation. How the IEC death is regulated to physiologically prevent intestinal inflammation needs further investigation. Here, we report that EF-hand domain-containing protein D2 (EFHD2), highly expressed in normal intestine tissues but decreased in intestinal biopsy samples of ulcerative colitis patients, protects intestinal epithelium from TNF-induced IEC apoptosis. EFHD2 inhibits TNF-induced apoptosis in primary IECs and intestinal organoids (enteroids). Mice deficient of Efhd2 in IECs exhibit excessive IEC death and exacerbated experimental colitis. Mechanistically, EFHD2 interacts with Cofilin and suppresses Cofilin phosphorylation, thus blocking TNF receptor I (TNFR1) internalization to inhibit IEC apoptosis and consequently protecting intestine from inflammation. Our findings deepen the understanding of EFHD2 as the key regulator of membrane receptor trafficking, providing insight into death receptor signals and autoinflammatory diseases.
    DOI:  https://doi.org/10.1038/s41467-024-45539-x
  7. Nat Commun. 2024 Feb 16. 15(1): 1434
    Reduced progranulin increases tau and α-synuclein inclusions and alters mouse tauopathy phenotypes via glucocerebrosidase.
    Hideyuki Takahashi, Sanaea Bhagwagar, Sarah H Nies, Hongping Ye, Xianlin Han, Marius T Chiasseu, Guilin Wang, Ian R Mackenzie, Stephen M Strittmatter.
      Comorbid proteinopathies are observed in many neurodegenerative disorders including Alzheimer's disease (AD), increase with age, and influence clinical outcomes, yet the mechanisms remain ill-defined. Here, we show that reduction of progranulin (PGRN), a lysosomal protein associated with TDP-43 proteinopathy, also increases tau inclusions, causes concomitant accumulation of α-synuclein and worsens mortality and disinhibited behaviors in tauopathy mice. The increased inclusions paradoxically protect against spatial memory deficit and hippocampal neurodegeneration. PGRN reduction in male tauopathy attenuates activity of β-glucocerebrosidase (GCase), a protein previously associated with synucleinopathy, while increasing glucosylceramide (GlcCer)-positive tau inclusions. In neuronal culture, GCase inhibition enhances tau aggregation induced by AD-tau. Furthermore, purified GlcCer directly promotes tau aggregation in vitro. Neurofibrillary tangles in human tauopathies are also GlcCer-immunoreactive. Thus, in addition to TDP-43, PGRN regulates tau- and synucleinopathies via GCase and GlcCer. A lysosomal PGRN-GCase pathway may be a common therapeutic target for age-related comorbid proteinopathies.
    DOI:  https://doi.org/10.1038/s41467-024-45692-3
  8. Nat Commun. 2024 Feb 13. 15(1): 1337
    TYK2 signaling promotes the development of autoreactive CD8+ cytotoxic T lymphocytes and type 1 diabetes.
    Keiichiro Mine, Seiho Nagafuchi, Satoru Akazawa, Norio Abiru, Hitoe Mori, Hironori Kurisaki, Kazuya Shimoda, Yasunobu Yoshikai, Hirokazu Takahashi, Keizo Anzai.
      Tyrosine kinase 2 (TYK2), a member of the JAK family, has attracted attention as a potential therapeutic target for autoimmune diseases. However, the role of TYK2 in CD8+ T cells and autoimmune type 1 diabetes (T1D) is poorly understood. In this study, we generate Tyk2 gene knockout non-obese diabetes (NOD) mice and demonstrate that the loss of Tyk2 inhibits the development of autoreactive CD8+ T-BET+ cytotoxic T lymphocytes (CTLs) by impairing IL-12 signaling in CD8+ T cells and the CD8+ resident dendritic cell-driven cross-priming of CTLs in the pancreatic lymph node (PLN). Tyk2-deficient CTLs display reduced cytotoxicity. Increased inflammatory responses in β-cells with aging are dampened by Tyk2 deficiency. Furthermore, treatment with BMS-986165, a selective TYK2 inhibitor, inhibits the expansion of T-BET+ CTLs, inflammation in β-cells and the onset of autoimmune T1D in NOD mice. Thus, our study reveals the diverse roles of TYK2 in driving the pathogenesis of T1D.
    DOI:  https://doi.org/10.1038/s41467-024-45573-9
  9. Nat Rev Immunol. 2024 Feb 13.
    Regulation goes awry in the liver.
    Yvonne Bordon.
      
    DOI:  https://doi.org/10.1038/s41577-024-01004-w
  10. Nat Rev Immunol. 2024 Feb 12.
    Neutrophils become pro-angiogenic in tumours.
    Lucy Bird.
      
    DOI:  https://doi.org/10.1038/s41577-024-01002-y
  11. Nat Immunol. 2024 Feb 13.
    Distinct ontogenetic lineages dictate cDC2 heterogeneity.
    Carlos M Minutti, Cécile Piot, Mariana Pereira da Costa, Probir Chakravarty, Neil Rogers, Hector Huerga Encabo, Ana Cardoso, Jane Loong, Gilles Bessou, Cyrille Mionnet, Jean Langhorne, Dominique Bonnet, Marc Dalod, Elena Tomasello, Caetano Reis E Sousa.
      Conventional dendritic cells (cDCs) include functionally and phenotypically diverse populations, such as cDC1s and cDC2s. The latter population has been variously subdivided into Notch-dependent cDC2s, KLF4-dependent cDC2s, T-bet+ cDC2As and T-bet- cDC2Bs, but it is unclear how all these subtypes are interrelated and to what degree they represent cell states or cell subsets. All cDCs are derived from bone marrow progenitors called pre-cDCs, which circulate through the blood to colonize peripheral tissues. Here, we identified distinct mouse pre-cDC2 subsets biased to give rise to cDC2As or cDC2Bs. We showed that a Siglec-H+ pre-cDC2A population in the bone marrow preferentially gave rise to Siglec-H- CD8α+ pre-cDC2As in tissues, which differentiated into T-bet+ cDC2As. In contrast, a Siglec-H- fraction of pre-cDCs in the bone marrow and periphery mostly generated T-bet- cDC2Bs, a lineage marked by the expression of LysM. Our results showed that cDC2A versus cDC2B fate specification starts in the bone marrow and suggest that cDC2 subsets are ontogenetically determined lineages, rather than cell states imposed by the peripheral tissue environment.
    DOI:  https://doi.org/10.1038/s41590-024-01745-9
  12. Nat Commun. 2024 Feb 12. 15(1): 1280
    Sonic hedgehog-heat shock protein 90β axis promotes the development of nonalcoholic steatohepatitis in mice.
    Weitao Zhang, Junfeng Lu, Lianshun Feng, Hanyue Xue, Shiyang Shen, Shuiqing Lai, PingPing Li, Ping Li, Jian Kuang, Zhiwei Yang, Xiaojun Xu.
      Sonic hedgehog (SHH) and heat shock protein 90β (HSP90β) have been implicated in nonalcoholic steatohepatitis (NASH) but their molecular mechanisms of action remain elusive. We find that HSP90β is a key SHH downstream molecule for promoting NASH process. In hepatocytes, SHH reduces HSP90β ubiquitylation through deubiquitylase USP31, thus preventing HSP90β degradation and promoting hepatic lipid synthesis. HSP90β significantly increases in NASH mouse model, leading to secretion of exosomes enriched with miR-28-5p. miR-28-5p directly targetes and decreases Rap1b levels, which in turn promotes NF-κB transcriptional activity in macrophages and stimulates the expression of inflammatory factors. Genetic deletion, pharmacological inhibition of the SHH-HSP90β axis, or delivery of miR-28-5p to macrophages in the male mice liver, impairs NASH symptomatic development. Importantly, there is a markedly higher abundance of miR-28-5p in NASH patient sera. Taken together, the SHH-HSP90β-miR-28-5p axis offers promising therapeutic targets against NASH, and serum miR-28-5p may serve as a NASH diagnostic biomarker.
    DOI:  https://doi.org/10.1038/s41467-024-45520-8
  13. Science. 2024 Feb 16. 383(6684): 705-707
    Decoding the autoantibody reactome.
    Jillian R Jaycox, Yile Dai, Aaron M Ring.
      Autoantibodies influence a wide range of conditions beyond autoimmune diseases.
    DOI:  https://doi.org/10.1126/science.abn1034
  14. Nat Aging. 2024 Feb 14.
    Home exergame prevents falls.
    Anna Kriebs.
      
    DOI:  https://doi.org/10.1038/s43587-024-00579-2
  15. Science. 2024 Feb 16. 383(6684): 703-705
    HIV cure: The daunting scale of the problem.
    Janet D Siliciano, Robert F Siliciano.
      Cure strategies are confounded by basic reservoir biology.
    DOI:  https://doi.org/10.1126/science.adk1831
  16. Nature. 2024 Feb 14.
    Genetic determinants of micronucleus formation in vivo.
    Sanger Mouse Genetics Project
      Genomic instability arising from defective responses to DNA damage1 or mitotic chromosomal imbalances2 can lead to the sequestration of DNA in aberrant extranuclear structures called micronuclei (MN). Although MN are a hallmark of ageing and diseases associated with genomic instability, the catalogue of genetic players that regulate the generation of MN remains to be determined. Here we analyse 997 mouse mutant lines, revealing 145 genes whose loss significantly increases (n = 71) or decreases (n = 74) MN formation, including many genes whose orthologues are linked to human disease. We found that mice null for Dscc1, which showed the most significant increase in MN, also displayed a range of phenotypes characteristic of patients with cohesinopathy disorders. After validating the DSCC1-associated MN instability phenotype in human cells, we used genome-wide CRISPR-Cas9 screening to define synthetic lethal and synthetic rescue interactors. We found that the loss of SIRT1 can rescue phenotypes associated with DSCC1 loss in a manner paralleling restoration of protein acetylation of SMC3. Our study reveals factors involved in maintaining genomic stability and shows how this information can be used to identify mechanisms that are relevant to human disease biology1.
    DOI:  https://doi.org/10.1038/s41586-023-07009-0
  17. Nat Commun. 2024 Feb 12. 15(1): 1290
    A spotlight on the tuberculosis epidemic in South Africa.
      
    DOI:  https://doi.org/10.1038/s41467-024-45491-w
  18. Dev Cell. 2024 Feb 06. pii: S1534-5807(24)00037-6. [Epub ahead of print]
    Lineage motifs as developmental modules for control of cell type proportions.
    Martin Tran, Amjad Askary, Michael B Elowitz.
      In multicellular organisms, cell types must be produced and maintained in appropriate proportions. One way this is achieved is through committed progenitor cells or extrinsic interactions that produce specific patterns of descendant cell types on lineage trees. However, cell fate commitment is probabilistic in most contexts, making it difficult to infer these dynamics and understand how they establish overall cell type proportions. Here, we introduce Lineage Motif Analysis (LMA), a method that recursively identifies statistically overrepresented patterns of cell fates on lineage trees as potential signatures of committed progenitor states or extrinsic interactions. Applying LMA to published datasets reveals spatial and temporal organization of cell fate commitment in zebrafish and rat retina and early mouse embryonic development. Comparative analysis of vertebrate species suggests that lineage motifs facilitate adaptive evolutionary variation of retinal cell type proportions. LMA thus provides insight into complex developmental processes by decomposing them into simpler underlying modules.
    Keywords:  blastocyst development; cell fate correlations; cell type proportions; committed progenitor; extrinsic interactions; lineage tree; motif analysis; retina development
    DOI:  https://doi.org/10.1016/j.devcel.2024.01.017
  19. Nat Rev Immunol. 2024 Feb 13.
    Human ILC2s can act as cytolytic killers.
    Maria Papatriantafyllou.
      
    DOI:  https://doi.org/10.1038/s41577-024-01005-9
  20. Mol Cell. 2024 Feb 06. pii: S1097-2765(24)00052-2. [Epub ahead of print]
    The HRI branch of the integrated stress response selectively triggers mitophagy.
    Yogaditya Chakrabarty, Zheng Yang, Hsiuchen Chen, David C Chan.
      To maintain mitochondrial homeostasis, damaged or excessive mitochondria are culled in coordination with the physiological state of the cell. The integrated stress response (ISR) is a signaling network that recognizes diverse cellular stresses, including mitochondrial dysfunction. Because the four ISR branches converge to common outputs, it is unclear whether mitochondrial stress detected by this network can regulate mitophagy, the autophagic degradation of mitochondria. Using a whole-genome screen, we show that the heme-regulated inhibitor (HRI) branch of the ISR selectively induces mitophagy. Activation of the HRI branch results in mitochondrial localization of phosphorylated eukaryotic initiation factor 2, which we show is sufficient to induce mitophagy. The HRI mitophagy pathway operates in parallel with the mitophagy pathway controlled by the Parkinson's disease related genes PINK1 and PARKIN and is mechanistically distinct. Therefore, HRI repurposes machinery that is normally used for translational initiation to trigger mitophagy in response to mitochondrial damage.
    Keywords:  autophagy; integrated stress response; iron metabolism; mitochondria; mitophagy; organelle quality control
    DOI:  https://doi.org/10.1016/j.molcel.2024.01.016
  21. Nat Commun. 2024 Feb 16. 15(1): 1429
    Pro-ferroptotic signaling promotes arterial aging via vascular smooth muscle cell senescence.
    Di-Yang Sun, Wen-Bin Wu, Jian-Jin Wu, Yu Shi, Jia-Jun Xu, Shen-Xi Ouyang, Chen Chi, Yi Shi, Qing-Xin Ji, Jin-Hao Miao, Jiang-Tao Fu, Jie Tong, Ping-Ping Zhang, Jia-Bao Zhang, Zhi-Yong Li, Le-Feng Qu, Fu-Ming Shen, Dong-Jie Li, Pei Wang.
      Senescence of vascular smooth muscle cells (VSMCs) contributes to aging-related cardiovascular diseases by promoting arterial remodelling and stiffness. Ferroptosis is a novel type of regulated cell death associated with lipid oxidation. Here, we show that pro-ferroptosis signaling drives VSMCs senescence to accelerate vascular NAD+ loss, remodelling and aging. Pro-ferroptotic signaling is triggered in senescent VSMCs and arteries of aged mice. Furthermore, the activation of pro-ferroptotic signaling in VSMCs not only induces NAD+ loss and senescence but also promotes the release of a pro-senescent secretome. Pharmacological or genetic inhibition of pro-ferroptosis signaling, ameliorates VSMCs senescence, reduces vascular stiffness and retards the progression of abdominal aortic aneurysm in mice. Mechanistically, we revealed that inhibition of pro-ferroptotic signaling facilitates the nuclear-cytoplasmic shuttling of proliferator-activated receptor-γ and, thereby impeding nuclear receptor coactivator 4-ferrtin complex-centric ferritinophagy. Finally, the activated pro-ferroptotic signaling correlates with arterial stiffness in a human proof-of-concept study. These findings have significant implications for future therapeutic strategies aiming to eliminate vascular ferroptosis in senescence- or aging-associated cardiovascular diseases.
    DOI:  https://doi.org/10.1038/s41467-024-45823-w
  22. Nat Commun. 2024 Feb 12. 15(1): 1311
    In situ structure of actin remodeling during glucose-stimulated insulin secretion using cryo-electron tomography.
    Weimin Li, Angdi Li, Bing Yu, Xiaoxiao Zhang, Xiaoyan Liu, Kate L White, Raymond C Stevens, Wolfgang Baumeister, Andrej Sali, Marion Jasnin, Liping Sun.
      Actin mediates insulin secretion in pancreatic β-cells through remodeling. Hampered by limited resolution, previous studies have offered an ambiguous depiction as depolymerization and repolymerization. We report the in situ structure of actin remodeling in INS-1E β-cells during glucose-stimulated insulin secretion at nanoscale resolution. After remodeling, the actin filament network at the cell periphery exhibits three marked differences: 12% of actin filaments reorient quasi-orthogonally to the ventral membrane; the filament network mainly remains as cell-stabilizing bundles but partially reconfigures into a less compact arrangement; actin filaments anchored to the ventral membrane reorganize from a "netlike" to a "blooming" architecture. Furthermore, the density of actin filaments and microtubules around insulin secretory granules decreases, while actin filaments and microtubules become more densely packed. The actin filament network after remodeling potentially precedes the transport and release of insulin secretory granules. These findings advance our understanding of actin remodeling and its role in glucose-stimulated insulin secretion.
    DOI:  https://doi.org/10.1038/s41467-024-45648-7
  23. Nat Neurosci. 2024 Feb 15.
    Hunger guides immunity to friend versus foe.
    Noga Or-Geva, Lawrence Steinman.
      
    DOI:  https://doi.org/10.1038/s41593-024-01590-x
  24. Science. 2024 Feb 16. 383(6684): 702-703
    Telomerase misbehaves after a breakup.
    Nausica Arnoult, Thomas R Cech.
      Suppressing telomerase action at broken DNA preserves genome integrity.
    DOI:  https://doi.org/10.1126/science.adn7791
  25. Nature. 2024 Feb 14.
    Autonomous transposons tune their sequences to ensure somatic suppression.
    İbrahim Avşar Ilık, Petar Glažar, Kevin Tse, Björn Brändl, David Meierhofer, Franz-Josef Müller, Zachary D Smith, Tuğçe Aktaş.
      Transposable elements (TEs) are a major constituent of human genes, occupying approximately half of the intronic space. During pre-messenger RNA synthesis, intronic TEs are transcribed along with their host genes but rarely contribute to the final mRNA product because they are spliced out together with the intron and rapidly degraded. Paradoxically, TEs are an abundant source of RNA-processing signals through which they can create new introns1, and also functional2 or non-functional chimeric transcripts3. The rarity of these events implies the existence of a resilient splicing code that is able to suppress TE exonization without compromising host pre-mRNA processing. Here we show that SAFB proteins protect genome integrity by preventing retrotransposition of L1 elements while maintaining splicing integrity, via prevention of the exonization of previously integrated TEs. This unique dual role is possible because of L1's conserved adenosine-rich coding sequences that are bound by SAFB proteins. The suppressive activity of SAFB extends to tissue-specific, giant protein-coding cassette exons, nested genes and Tigger DNA transposons. Moreover, SAFB also suppresses LTR/ERV elements in species in which they are still active, such as mice and flies. A significant subset of splicing events suppressed by SAFB in somatic cells are activated in the testis, coinciding with low SAFB expression in postmeiotic spermatids. Reminiscent of the division of labour between innate and adaptive immune systems that fight external pathogens, our results uncover SAFB proteins as an RNA-based, pattern-guided, non-adaptive defence system against TEs in the soma, complementing the RNA-based, adaptive Piwi-interacting RNA pathway of the germline.
    DOI:  https://doi.org/10.1038/s41586-024-07081-0
  26. Nat Commun. 2024 Feb 13. 15(1): 1314
    HKDC1 promotes tumor immune evasion in hepatocellular carcinoma by coupling cytoskeleton to STAT1 activation and PD-L1 expression.
    Yi Zhang, Mingjie Wang, Ling Ye, Shengqi Shen, Yuxi Zhang, Xiaoyu Qian, Tong Zhang, Mengqiu Yuan, Zijian Ye, Jin Cai, Xiang Meng, Shiqiao Qiu, Shengzhi Liu, Rui Liu, Weidong Jia, Xianzhu Yang, Huafeng Zhang, Xiuying Zhong, Ping Gao.
      Immune checkpoint blockade (ICB) has shown considerable promise for treating various malignancies, but only a subset of cancer patients benefit from immune checkpoint inhibitor therapy because of immune evasion and immune-related adverse events (irAEs). The mechanisms underlying how tumor cells regulate immune cell response remain largely unknown. Here we show that hexokinase domain component 1 (HKDC1) promotes tumor immune evasion in a CD8+ T cell-dependent manner by activating STAT1/PD-L1 in tumor cells. Mechanistically, HKDC1 binds to and presents cytosolic STAT1 to IFNGR1 on the plasma membrane following IFNγ-stimulation by associating with cytoskeleton protein ACTA2, resulting in STAT1 phosphorylation and nuclear translocation. HKDC1 inhibition in combination with anti-PD-1/PD-L1 enhances in vivo T cell antitumor response in liver cancer models in male mice. Clinical sample analysis indicates a correlation among HKDC1 expression, STAT1 phosphorylation, and survival in patients with hepatocellular carcinoma treated with atezolizumab (anti-PD-L1). These findings reveal a role for HKDC1 in regulating immune evasion by coupling cytoskeleton with STAT1 activation, providing a potential combination strategy to enhance antitumor immune responses.
    DOI:  https://doi.org/10.1038/s41467-024-45712-2
  27. J Clin Invest. 2024 Feb 13. pii: e171154. [Epub ahead of print]
    PD-1 and CTLA-4 blockade promote CD86-driven Treg responses upon radiotherapy of lymphocyte-depleted cancer in mice.
    Elselien Frijlink, Douwe Mt Bosma, Julia Busselaar, Thomas W Battaglia, Mo D Staal, Inge Verbrugge, Jannie Borst.
      Radiotherapy (RT) is considered immunogenic, but clinical data demonstrating RT-induced T-cell priming are scarce. Here, we show in a mouse tumor model representative of human lymphocyte-depleted cancer that RT enhances spontaneous priming of thymus-derived (FOXP3+ Helios+) regulatory T-cells (Tregs) by the tumor. These Tregs acquire an effector phenotype, populate the tumor and impede tumor control by a simultaneous, RT-induced CD8+ cytotoxic T-cell (CTL) response. Combination of RT with CTLA-4 or PD-1 blockade, which enables CD28 costimulation, further increased this Treg response and failed to improve tumor control. We discovered that upon RT, CD28-ligands CD86 and CD80 differentially affected the Treg response. CD86, but not CD80, blockade prevented the effector (e)Treg response, enriched the tumor-draining lymph node for PD-L1+CD80+ migratory, conventional dendritic cells (cDCs) and promoted CTL priming. Blockade of CD86 alone or in combination with PD-1, enhanced intra-tumoral CTL accumulation and the combination significantly increased RT-induced tumor regression and overall survival. We advise that combining RT with PD-1 and/or CTLA-4 blockade may be counterproductive in lymphocyte-depleted cancers, since they drive Treg responses in this context. However, combining RT with CD86 blockade may promote control of such tumors by enabling a CTL response.
    Keywords:  Cancer immunotherapy; Costimulation; Immunology; Oncology; Radiation therapy
    DOI:  https://doi.org/10.1172/JCI171154
  28. Nat Commun. 2024 Feb 16. 15(1): 1454
    A system for inducible mitochondria-specific protein degradation in vivo.
    Swastika Sanyal, Anna Kouznetsova, Lena Ström, Camilla Björkegren.
      Targeted protein degradation systems developed for eukaryotes employ cytoplasmic machineries to perform proteolysis. This has prevented mitochondria-specific analysis of proteins that localize to multiple locations, for example, the mitochondria and the nucleus. Here, we present an inducible mitochondria-specific protein degradation system in Saccharomyces cerevisiae based on the Mesoplasma florum Lon (mf-Lon) protease and its corresponding ssrA tag (called PDT). We show that mitochondrially targeted mf-Lon protease efficiently and selectively degrades a PDT-tagged reporter protein localized to the mitochondrial matrix. The degradation can be induced by depleting adenine from the medium, and tuned by altering the promoter strength of the MF-LON gene. We furthermore demonstrate that mf-Lon specifically degrades endogenous, PDT-tagged mitochondrial proteins. Finally, we show that mf-Lon-dependent PDT degradation can also be achieved in human mitochondria. In summary, this system provides an efficient tool to selectively analyze the mitochondrial function of dually localized proteins.
    DOI:  https://doi.org/10.1038/s41467-024-45819-6
  29. Nat Commun. 2024 Feb 15. 15(1): 1391
    Adipocyte p53 coordinates the response to intermittent fasting by regulating adipose tissue immune cell landscape.
    Isabel Reinisch, Helene Michenthaler, Alba Sulaj, Elisabeth Moyschewitz, Jelena Krstic, Markus Galhuber, Ruonan Xu, Zina Riahi, Tongtong Wang, Nemanja Vujic, Melina Amor, Riccardo Zenezini Chiozzi, Martin Wabitsch, Dagmar Kolb, Anastasia Georgiadi, Lisa Glawitsch, Ellen Heitzer, Tim J Schulz, Michael Schupp, Wenfei Sun, Hua Dong, Adhideb Ghosh, Anne Hoffmann, Dagmar Kratky, Laura C Hinte, Ferdinand von Meyenn, Albert J R Heck, Matthias Blüher, Stephan Herzig, Christian Wolfrum, Andreas Prokesch.
      In obesity, sustained adipose tissue (AT) inflammation constitutes a cellular memory that limits the effectiveness of weight loss interventions. Yet, the impact of fasting regimens on the regulation of AT immune infiltration is still elusive. Here we show that intermittent fasting (IF) exacerbates the lipid-associated macrophage (LAM) inflammatory phenotype of visceral AT in obese mice. Importantly, this increase in LAM abundance is strongly p53 dependent and partly mediated by p53-driven adipocyte apoptosis. Adipocyte-specific deletion of p53 prevents LAM accumulation during IF, increases the catabolic state of adipocytes, and enhances systemic metabolic flexibility and insulin sensitivity. Finally, in cohorts of obese/diabetic patients, we describe a p53 polymorphism that links to efficacy of a fasting-mimicking diet and that the expression of p53 and TREM2 in AT negatively correlates with maintaining weight loss after bariatric surgery. Overall, our results demonstrate that p53 signalling in adipocytes dictates LAM accumulation in AT under IF and modulates fasting effectiveness in mice and humans.
    DOI:  https://doi.org/10.1038/s41467-024-45724-y
  30. Nat Cell Biol. 2024 Feb 15.
    Order and disorder in clathrin-mediated endocytosis.
      
    DOI:  https://doi.org/10.1038/s41556-024-01355-5
  31. Nat Rev Immunol. 2024 Feb 13.
    Complement in maternal milk shapes the infant microbiome.
    Maria Papatriantafyllou.
      
    DOI:  https://doi.org/10.1038/s41577-024-01006-8
  32. Nat Commun. 2024 Feb 10. 15(1): 1261
    A hepatic network of dendritic cells mediates CD4 T cell help outside lymphoid organs.
    Kieran English, Rain Kwan, Lauren E Holz, Claire McGuffog, Jelte M M Krol, Daryan Kempe, Tsuneyasu Kaisho, William R Heath, Leszek Lisowski, Maté Biro, Geoffrey W McCaughan, David G Bowen, Patrick Bertolino.
      While CD4+ T cells are a prerequisite for CD8+ T cell-mediated protection against intracellular hepatotropic pathogens, the mechanisms facilitating the transfer of CD4-help to intrahepatic CD8+ T cells are unknown. Here, we developed an experimental system to investigate cognate CD4+ and CD8+ T cell responses to a model-antigen expressed de novo in hepatocytes and reveal that after initial priming, effector CD4+ and CD8+ T cells migrate into portal tracts and peri-central vein regions of the liver where they cluster with type-1 conventional dendritic cells. These dendritic cells are locally licensed by CD4+ T cells and expand the number of CD8+ T cells in situ, resulting in larger effector and memory CD8+ T cell pools. These findings reveal that CD4+ T cells promote intrahepatic immunity by amplifying the CD8+ T cell response via peripheral licensing of hepatic type-1 conventional dendritic cells and identify intrahepatic perivascular compartments specialized in facilitating effector T cell-dendritic cell interactions.
    DOI:  https://doi.org/10.1038/s41467-024-45612-5
  33. Science. 2024 Feb 16. 383(6684): 714
    Who goes there?
    Carla Nowosad.
      How B cells assess risk in the intestine.
    DOI:  https://doi.org/10.1126/science.adn9414
  34. Nat Commun. 2024 Feb 10. 15(1): 1247
    Heterogeneity of hepatocyte dynamics restores liver architecture after chemical, physical or viral damage.
    Inmaculada Ruz-Maldonado, John T Gonzalez, Hanming Zhang, Jonathan Sun, Alicia Bort, Inamul Kabir, Richard G Kibbey, Yajaira Suárez, Daniel M Greif, Carlos Fernández-Hernando.
      Midlobular hepatocytes are proposed to be the most plastic hepatic cell, providing a reservoir for hepatocyte proliferation during homeostasis and regeneration. However, other mechanisms beyond hyperplasia have been little explored and the contribution of other hepatocyte subpopulations to regeneration has been controversial. Thus, re-examining hepatocyte dynamics during regeneration is critical for cell therapy and treatment of liver diseases. Using a mouse model of hepatocyte- and non-hepatocyte- multicolor lineage tracing, we demonstrate that midlobular hepatocytes also undergo hypertrophy in response to chemical, physical, and viral insults. Our study shows that this subpopulation also combats liver impairment after infection with coronavirus. Furthermore, we demonstrate that pericentral hepatocytes also expand in number and size during the repair process and Galectin-9-CD44 pathway may be critical for driving these processes. Notably, we also identified that transdifferentiation and cell fusion during regeneration after severe injury contribute to recover hepatic function.
    DOI:  https://doi.org/10.1038/s41467-024-45439-0
  35. Nat Commun. 2024 Feb 14. 15(1): 1364
    Sequential stacking link prediction algorithms for temporal networks.
    Xie He, Amir Ghasemian, Eun Lee, Aaron Clauset, Peter J Mucha.
      Link prediction algorithms are indispensable tools in many scientific applications by speeding up network data collection and imputing missing connections. However, in many systems, links change over time and it remains unclear how to optimally exploit such temporal information for link predictions in such networks. Here, we show that many temporal topological features, in addition to having high computational cost, are less accurate in temporal link prediction than sequentially stacked static network features. This sequential stacking link prediction method uses 41 static network features that avoid detailed feature engineering choices and is capable of learning a highly accurate predictive distribution of future connections from historical data. We demonstrate that this algorithm works well for both partially observed and completely unobserved target layers, and on two temporal stochastic block models achieves near-oracle-level performance when combined with other single predictor methods as an ensemble learning method. Finally, we empirically illustrate that stacking multiple predictive methods together further improves performance on 19 real-world temporal networks from different domains.
    DOI:  https://doi.org/10.1038/s41467-024-45598-0
  36. Nat Aging. 2024 Feb 12.
    Blood protein markers predict 15-year risk of dementia.
      
    DOI:  https://doi.org/10.1038/s43587-023-00566-z
  37. Nat Immunol. 2024 Feb 14.
    Reactivating antitumor immunity by inhibiting JMJD1C.
    Xuezheng Wang, Keji Zhao.
      
    DOI:  https://doi.org/10.1038/s41590-024-01760-w
  38. Cell Rep. 2024 Feb 15. pii: S2211-1247(24)00120-7. [Epub ahead of print]43(2): 113792
    The HIF transcription network exerts innate antiviral activity in neurons and limits brain inflammation.
    Ensieh Farahani, Line S Reinert, Ryo Narita, Manutea C Serrero, Morten Kelder Skouboe, Demi van der Horst, Sonia Assil, Baocun Zhang, Marie B Iversen, Eugenio Gutierrez, Hossein Hazrati, Mogens Johannsen, David Olagnier, Reiner Kunze, Mark Denham, Trine H Mogensen, Michael Lappe, Søren R Paludan.
      Pattern recognition receptors (PRRs) induce host defense but can also induce exacerbated inflammatory responses. This raises the question of whether other mechanisms are also involved in early host defense. Using transcriptome analysis of disrupted transcripts in herpes simplex virus (HSV)-infected cells, we find that HSV infection disrupts the hypoxia-inducible factor (HIF) transcription network in neurons and epithelial cells. Importantly, HIF activation leads to control of HSV replication. Mechanistically, HIF activation induces autophagy, which is essential for antiviral activity. HSV-2 infection in vivo leads to hypoxia in CNS neurons, and mice with neuron-specific HIF1/2α deficiency exhibit elevated viral load and augmented PRR signaling and inflammatory gene expression in the CNS after HSV-2 infection. Data from human stem cell-derived neuron and microglia cultures show that HIF also exerts antiviral and inflammation-restricting activity in human CNS cells. Collectively, the HIF transcription factor system senses virus-induced hypoxic stress to induce cell-intrinsic antiviral responses and limit inflammation.
    Keywords:  CP: Immunology; CP: Microbiology; HIF; herpes simplex virus; immune evasion; immune regulation; innate antiviral defense; neurons
    DOI:  https://doi.org/10.1016/j.celrep.2024.113792
  39. Nature. 2024 Feb 12.
    Early dementia diagnosis: blood proteins reveal at-risk people.
    Miryam Naddaf.
      
    Keywords:  Alzheimer's disease; Brain; Neurodegeneration; Neuroscience
    DOI:  https://doi.org/10.1038/d41586-024-00418-9
  40. Mol Cell. 2024 Feb 06. pii: S1097-2765(24)00055-8. [Epub ahead of print]
    Persistence of backtracking by human RNA polymerase II.
    Kevin B Yang, Aviram Rasouly, Vitaly Epshtein, Criseyda Martinez, Thao Nguyen, Ilya Shamovsky, Evgeny Nudler.
      RNA polymerase II (RNA Pol II) can backtrack during transcription elongation, exposing the 3' end of nascent RNA. Nascent RNA sequencing can approximate the location of backtracking events that are quickly resolved; however, the extent and genome-wide distribution of more persistent backtracking are unknown. Consequently, we developed a method to directly sequence the extruded, "backtracked" 3' RNA. Our data show that RNA Pol II slides backward more than 20 nt in human cells and can persist in this backtracked state. Persistent backtracking mainly occurs where RNA Pol II pauses near promoters and intron-exon junctions and is enriched in genes involved in translation, replication, and development, where gene expression is decreased if these events are unresolved. Histone genes are highly prone to persistent backtracking, and the resolution of such events is likely required for timely expression during cell division. These results demonstrate that persistent backtracking can potentially affect diverse gene expression programs.
    Keywords:  RNA polymerase II; backtracking; gene regulation; histone genes; transcription elongation
    DOI:  https://doi.org/10.1016/j.molcel.2024.01.019
  41. Nat Commun. 2024 Feb 15. 15(1): 1405
    Cell softness renders cytotoxic T lymphocytes and T leukemic cells resistant to perforin-mediated killing.
    Yabo Zhou, Dianheng Wang, Li Zhou, Nannan Zhou, Zhenfeng Wang, Jie Chen, Ruiyang Pang, Haixia Fu, Qiusha Huang, Fang Dong, Hui Cheng, Huafeng Zhang, Ke Tang, Jingwei Ma, Jiadi Lv, Tao Cheng, Roland Fiskesund, Xiaohui Zhang, Bo Huang.
      Mechanical force contributes to perforin pore formation at immune synapses, thus facilitating the cytotoxic T lymphocytes (CTL)-mediated killing of tumor cells in a unidirectional fashion. How such mechanical cues affect CTL evasion of perforin-mediated autolysis remains unclear. Here we show that activated CTLs use their softness to evade perforin-mediated autolysis, which, however, is shared by T leukemic cells to evade CTL killing. Downregulation of filamin A is identified to induce softness via ZAP70-mediated YAP Y357 phosphorylation and activation. Despite the requirements of YAP in both cell types for softness induction, CTLs are more resistant to YAP inhibitors than malignant T cells, potentially due to the higher expression of the drug-resistant transporter, MDR1, in CTLs. As a result, moderate inhibition of YAP stiffens malignant T cells but spares CTLs, thus allowing CTLs to cytolyze malignant cells without autolysis. Our findings thus hint a mechanical force-based immunotherapeutic strategy against T cell leukemia.
    DOI:  https://doi.org/10.1038/s41467-024-45750-w
  42. Nat Aging. 2024 Feb 14.
    Immunodeficiency disease linked to cell senescence.
    Hannah Walters.
      
    DOI:  https://doi.org/10.1038/s43587-024-00582-7
  43. Nat Commun. 2024 Feb 13. 15(1): 1297
    Cryo-EM structures of lipidic fibrils of amyloid-β (1-40).
    Benedikt Frieg, Mookyoung Han, Karin Giller, Christian Dienemann, Dietmar Riedel, Stefan Becker, Loren B Andreas, Christian Griesinger, Gunnar F Schröder.
      Alzheimer's disease (AD) is a progressive and incurable neurodegenerative disease characterized by the extracellular deposition of amyloid plaques. Investigation into the composition of these plaques revealed a high amount of amyloid-β (Aβ) fibrils and a high concentration of lipids, suggesting that fibril-lipid interactions may also be relevant for the pathogenesis of AD. Therefore, we grew Aβ40 fibrils in the presence of lipid vesicles and determined their structure by cryo-electron microscopy (cryo-EM) to high resolution. The fold of the major polymorph is similar to the structure of brain-seeded fibrils reported previously. The majority of the lipids are bound to the fibrils, as we show by cryo-EM and NMR spectroscopy. This apparent lipid extraction from vesicles observed here in vitro provides structural insights into potentially disease-relevant fibril-lipid interactions.
    DOI:  https://doi.org/10.1038/s41467-023-43822-x
  44. Cell Death Dis. 2024 Feb 14. 15(2): 140
    Innate and adaptive immune cell interaction drives inflammasome activation and hepatocyte apoptosis in murine liver injury from immune checkpoint inhibitors.
    Layla Shojaie, Jacob M Bogdanov, Helia Alavifard, Mahmoud G Mohamed, Aria Baktash, Myra Ali, Simeon Mahov, Sue Murray, Gary C Kanel, Zhang-Xu Liu, Fumito Ito, Gino K In, Akil Merchant, William Stohl, Lily Dara.
      Immune checkpoints (CTLA4 & PD-1) are inhibitory pathways that block aberrant immune activity and maintain self-tolerance. Tumors co-opt these checkpoints to avoid immune destruction. Immune checkpoint inhibitors (ICIs) activate immune cells and restore their tumoricidal potential, making them highly efficacious cancer therapies. However, immunotolerant organs such as the liver depend on these tolerogenic mechanisms, and their disruption with ICI use can trigger the unintended side effect of hepatotoxicity termed immune-mediated liver injury from ICIs (ILICI). Learning how to uncouple ILICI from ICI anti-tumor activity is of paramount clinical importance. We developed a murine model to recapitulate human ILICI using CTLA4+/- mice treated with either combined anti-CTLA4 + anti-PDL1 or IgG1 + IgG2. We tested two forms of antisense oligonucleotides to knockdown caspase-3 in a total liver (parenchymal and non-parenchymal cells) or in a hepatocyte-specific manner. We also employed imaging mass cytometry (IMC), a powerful multiplex modality for immunophenotyping and cell interaction analysis in our model. ICI-treated mice had significant evidence of liver injury. We detected cleaved caspase-3 (cC3), indicating apoptosis was occurring, as well as Nod-like receptor protein 3 (NLRP3) inflammasome activation, but no necroptosis. Total liver knockdown of caspase-3 worsened liver injury, and induced further inflammasome activation, and Gasdermin-D-mediated pyroptosis. Hepatocyte-specific knockdown of caspase-3 reduced liver injury and NLRP3 inflammasome activation. IMC-generated single-cell data for 77,692 cells was used to identify 22 unique phenotypic clusters. Spatial analysis revealed that cC3+ hepatocytes had significantly closer interactions with macrophages, Kupffer cells, and NLRP3hi myeloid cells than other cell types. We also observed zones of three-way interaction between cC3+ hepatocytes, CD8 + T-cells, and macrophages. Our work is the first to identify hepatocyte apoptosis and NLRP3 inflammasome activation as drivers of ILICI. Furthermore, we report that the interplay between adaptive and innate immune cells is critical to hepatocyte apoptosis and ILICI.
    DOI:  https://doi.org/10.1038/s41419-024-06535-7
  45. Nature. 2024 Feb 16.
    Move over, CRISPR: RNA-editing therapies pick up steam.
    Mariana Lenharo.
      
    Keywords:  CRISPR-Cas9 genome editing; Diseases; Genomics; Medical research
    DOI:  https://doi.org/10.1038/d41586-024-00275-6
  46. Nat Commun. 2024 Feb 14. 15(1): 1348
    TGF-β blockade drives a transitional effector phenotype in T cells reversing SIV latency and decreasing SIV reservoirs in vivo.
    Jinhee Kim, Deepanwita Bose, Mariluz Araínga, Muhammad R Haque, Christine M Fennessey, Rachel A Caddell, Yanique Thomas, Douglas E Ferrell, Syed Ali, Emanuelle Grody, Yogesh Goyal, Claudia Cicala, James Arthos, Brandon F Keele, Monica Vaccari, Ramon Lorenzo-Redondo, Thomas J Hope, Francois Villinger, Elena Martinelli.
      HIV-1 persistence during ART is due to the establishment of long-lived viral reservoirs in resting immune cells. Using an NHP model of barcoded SIVmac239 intravenous infection and therapeutic dosing of anti-TGFBR1 inhibitor galunisertib (LY2157299), we confirm the latency reversal properties of in vivo TGF-β blockade, decrease viral reservoirs and stimulate immune responses. Treatment of eight female, SIV-infected macaques on ART with four 2-weeks cycles of galunisertib leads to viral reactivation as indicated by plasma viral load and immunoPET/CT with a 64Cu-DOTA-F(ab')2-p7D3-probe. Post-galunisertib, lymph nodes, gut and PBMC exhibit lower cell-associated (CA-)SIV DNA and lower intact pro-virus (PBMC). Galunisertib does not lead to systemic increase in inflammatory cytokines. High-dimensional cytometry, bulk, and single-cell (sc)RNAseq reveal a galunisertib-driven shift toward an effector phenotype in T and NK cells characterized by a progressive downregulation in TCF1. In summary, we demonstrate that galunisertib, a clinical stage TGF-β inhibitor, reverses SIV latency and decreases SIV reservoirs by driving T cells toward an effector phenotype, enhancing immune responses in vivo in absence of toxicity.
    DOI:  https://doi.org/10.1038/s41467-024-45555-x
  47. Nat Commun. 2024 Feb 12. 15(1): 1286
    Chromatin attachment to the nuclear matrix represses hypocotyl elongation in Arabidopsis thaliana.
    Linhao Xu, Shiwei Zheng, Katja Witzel, Eveline Van De Slijke, Alexandra Baekelandt, Evelien Mylle, Daniel Van Damme, Jinping Cheng, Geert De Jaeger, Dirk Inzé, Hua Jiang.
      The nuclear matrix is a nuclear compartment that has diverse functions in chromatin regulation and transcription. However, how this structure influences epigenetic modifications and gene expression in plants is largely unknown. In this study, we show that a nuclear matrix binding protein, AHL22, together with the two transcriptional repressors FRS7 and FRS12, regulates hypocotyl elongation by suppressing the expression of a group of genes known as SMALL AUXIN UP RNAs (SAURs) in Arabidopsis thaliana. The transcriptional repression of SAURs depends on their attachment to the nuclear matrix. The AHL22 complex not only brings these SAURs, which contain matrix attachment regions (MARs), to the nuclear matrix, but it also recruits the histone deacetylase HDA15 to the SAUR loci. This leads to the removal of H3 acetylation at the SAUR loci and the suppression of hypocotyl elongation. Taken together, our results indicate that MAR-binding proteins act as a hub for chromatin and epigenetic regulators. Moreover, we present a mechanism by which nuclear matrix attachment to chromatin regulates histone modifications, transcription, and hypocotyl elongation.
    DOI:  https://doi.org/10.1038/s41467-024-45577-5
  48. Nat Cardiovasc Res. 2024 Jan;3(1): 60-75
    Suppression of IL-1β promotes beneficial accumulation of fibroblast-like cells in atherosclerotic plaques in clonal hematopoiesis.
    Trevor P Fidler, Andrew Dunbar, Eunyoung Kim, Brian Hardaway, Jessica Pauli, Chenyi Xue, Sandra Abramowicz, Tong Xiao, Kavi O'Connor, Nadja Sachs, Nan Wang, Lars Maegdefessel, Ross Levine, Muredach Reilly, Alan R Tall.
      Clonal hematopoiesis (CH) is an independent risk factor for atherosclerotic cardiovascular disease. Murine models of CH suggest a central role of inflammasomes and IL-1β in accelerated atherosclerosis and plaque destabilization. Here we show using single-cell RNA sequencing in human carotid plaques that inflammasome components are enriched in macrophages, while the receptor for IL-1β is enriched in fibroblasts and smooth muscle cells (SMCs). To address the role of inflammatory crosstalk in features of plaque destabilization, we conducted SMC fate mapping in Ldlr-/- mice modeling Jak2VF or Tet2 CH treated with IL-1β antibodies. Unexpectedly, this treatment minimally affected SMC differentiation, leading instead to a prominent expansion of fibroblast-like cells. Depletion of fibroblasts from mice treated with IL-1β antibody resulted in thinner fibrous caps. Conversely, genetic inactivation of Jak2VF during plaque regression promoted fibroblast accumulation and fibrous cap thickening. Our studies suggest that suppression of inflammasomes promotes plaque stabilization by recruiting fibroblast-like cells to the fibrous cap.
    DOI:  https://doi.org/10.1038/s44161-023-00405-9
  49. Nat Med. 2024 Feb 14.
    Validation of biomarkers of aging.
    Mahdi Moqri, Chiara Herzog, Jesse R Poganik, Kejun Ying, Jamie N Justice, Daniel W Belsky, Albert T Higgins-Chen, Brian H Chen, Alan A Cohen, Georg Fuellen, Sara Hägg, Riccardo E Marioni, Martin Widschwendter, Kristen Fortney, Peter O Fedichev, Alex Zhavoronkov, Nir Barzilai, Jessica Lasky-Su, Douglas P Kiel, Brian K Kennedy, Steven Cummings, P Eline Slagboom, Eric Verdin, Andrea B Maier, Vittorio Sebastiano, Michael P Snyder, Vadim N Gladyshev, Steve Horvath, Luigi Ferrucci.
      The search for biomarkers that quantify biological aging (particularly 'omic'-based biomarkers) has intensified in recent years. Such biomarkers could predict aging-related outcomes and could serve as surrogate endpoints for the evaluation of interventions promoting healthy aging and longevity. However, no consensus exists on how biomarkers of aging should be validated before their translation to the clinic. Here, we review current efforts to evaluate the predictive validity of omic biomarkers of aging in population studies, discuss challenges in comparability and generalizability and provide recommendations to facilitate future validation of biomarkers of aging. Finally, we discuss how systematic validation can accelerate clinical translation of biomarkers of aging and their use in gerotherapeutic clinical trials.
    DOI:  https://doi.org/10.1038/s41591-023-02784-9
  50. Annu Rev Physiol. 2024 Feb 12. 86 199-223
    Orchestration of the Adipose Tissue Immune Landscape by Adipocytes.
    David Bradley, Tuo Deng, Dharti Shantaram, Willa A Hsueh.
      Obesity is epidemic and of great concern because of its comorbid and costly inflammatory-driven complications. Extensive investigations in mice have elucidated highly coordinated, well-balanced interactions between adipocytes and immune cells in adipose tissue that maintain normal systemic metabolism in the lean state, while in obesity, proinflammatory changes occur in nearly all adipose tissue immune cells. Many of these changes are instigated by adipocytes. However, less is known about obesity-induced adipose-tissue immune cell alterations in humans. Upon high-fat diet feeding, the adipocyte changes its well-known function as a metabolic cell to assume the role of an immune cell, orchestrating proinflammatory changes that escalate inflammation and progress during obesity. This transformation is particularly prominent in humans. In this review, we (a) highlight a leading and early role for adipocytes in promulgating inflammation, (b) discuss immune cell changes and the time course of these changes (comparing humans and mice when possible), and (c) note how reversing proinflammatory changes in most types of immune cells, including adipocytes, rescues adipose tissue from inflammation and obese mice from insulin resistance.
    Keywords:  T cells; adipocyte; adipose tissue; inflammation; macrophages; neutrophils
    DOI:  https://doi.org/10.1146/annurev-physiol-042222-024353
  51. Nat Methods. 2024 Feb 12.
    TISSUE: uncertainty-calibrated prediction of single-cell spatial transcriptomics improves downstream analyses.
    Eric D Sun, Rong Ma, Paloma Navarro Negredo, Anne Brunet, James Zou.
      Whole-transcriptome spatial profiling of genes at single-cell resolution remains a challenge. To address this limitation, spatial gene expression prediction methods have been developed to infer the spatial expression of unmeasured transcripts, but the quality of these predictions can vary greatly. Here we present Transcript Imputation with Spatial Single-cell Uncertainty Estimation (TISSUE) as a general framework for estimating uncertainty for spatial gene expression predictions and providing uncertainty-aware methods for downstream inference. Leveraging conformal inference, TISSUE provides well-calibrated prediction intervals for predicted expression values across 11 benchmark datasets. Moreover, it consistently reduces the false discovery rate for differential gene expression analysis, improves clustering and visualization of predicted spatial transcriptomics and improves the performance of supervised learning models trained on predicted gene expression profiles. Applying TISSUE to a MERFISH spatial transcriptomics dataset of the adult mouse subventricular zone, we identified subtypes within the neural stem cell lineage and developed subtype-specific regional classifiers.
    DOI:  https://doi.org/10.1038/s41592-024-02184-y
  52. Nat Struct Mol Biol. 2024 Feb 12.
    Single-nucleoid architecture reveals heterogeneous packaging of mitochondrial DNA.
    R Stefan Isaac, Thomas W Tullius, Katja G Hansen, Danilo Dubocanin, Mary Couvillion, Andrew B Stergachis, L Stirling Churchman.
      Cellular metabolism relies on the regulation and maintenance of mitochondrial DNA (mtDNA). Hundreds to thousands of copies of mtDNA exist in each cell, yet because mitochondria lack histones or other machinery important for nuclear genome compaction, it remains unresolved how mtDNA is packaged into individual nucleoids. In this study, we used long-read single-molecule accessibility mapping to measure the compaction of individual full-length mtDNA molecules at near single-nucleotide resolution. We found that, unlike the nuclear genome, human mtDNA largely undergoes all-or-none global compaction, with most nucleoids existing in an inaccessible, inactive state. Highly accessible mitochondrial nucleoids are co-occupied by transcription and replication components and selectively form a triple-stranded displacement loop structure. In addition, we showed that the primary nucleoid-associated protein TFAM directly modulates the fraction of inaccessible nucleoids both in vivo and in vitro, acting consistently with a nucleation-and-spreading mechanism to coat and compact mitochondrial nucleoids. Together, these findings reveal the primary architecture of mtDNA packaging and regulation in human cells.
    DOI:  https://doi.org/10.1038/s41594-024-01225-6
  53. Nat Metab. 2024 Feb 13.
    Selenium abandons selenoproteins to inhibit ferroptosis rapidly.
    Ian G Chambers, Rajiv R Ratan.
      
    DOI:  https://doi.org/10.1038/s42255-024-00980-6
  54. Proc Natl Acad Sci U S A. 2024 Feb 20. 121(8): e2314561121
    Methyltransferase Setd2 prevents T cell-mediated autoimmune diseases via phospholipid remodeling.
    Yali Chen, Kun Chen, Ha Zhu, Hua Qin, Juan Liu, Xuetao Cao.
      Coordinated metabolic reprogramming and epigenetic remodeling are critical for modulating T cell function and differentiation. However, how the epigenetic modification controls Th17/Treg cell balance via metabolic reprogramming remains obscure. Here, we find that Setd2, a histone H3K36 trimethyltransferase, suppresses Th17 development but promotes iTreg cell polarization via phospholipid remodeling. Mechanistically, Setd2 up-regulates transcriptional expression of lysophosphatidylcholine acyltransferase 4 (Lpcat4) via directly catalyzing H3K36me3 of Lpcat4 gene promoter in T cells. Lpcat4-mediated phosphatidylcholine PC(16:0,18:2) generation in turn limits endoplasmic reticulum stress and oxidative stress. These changes decrease HIF-1α transcriptional activity and thus suppress Th17 but enhance Treg development. Consistent with this regulatory paradigm, T cell deficiency of Setd2 aggravates neuroinflammation and demyelination in experimental autoimmune encephalomyelitis due to imbalanced Th17/Treg cell differentiation. Overall, our data reveal that Setd2 acts as an epigenetic brake for T cell-mediated autoimmunity through phospholipid remodeling, suggesting potential targets for treating neuroinflammatory diseases.
    Keywords:  Setd2; autoimmunity; lysophosphatidylcholine acyltransferase 4; phosphatidylcholine
    DOI:  https://doi.org/10.1073/pnas.2314561121
  55. Nat Genet. 2024 Feb;56(2): 194
    Linking host genetics to gut microbial variation.
    Wei Li.
      
    DOI:  https://doi.org/10.1038/s41588-024-01672-3
  56. Nature. 2024 Feb 14.
    Structure of human phagocyte NADPH oxidase in the activated state.
    Xiaoyu Liu, Yiting Shi, Rui Liu, Kangcheng Song, Lei Chen.
      Phagocyte NADPH oxidase, a protein complex with a core made up of NOX2 and p22 subunits, is responsible for transferring electrons from intracellular NADPH to extracellular oxygen1. This process generates superoxide anions that are vital for killing pathogens1. The activation of phagocyte NADPH oxidase requires membrane translocation and the binding of several cytosolic factors2. However, the exact mechanism by which cytosolic factors bind to and activate NOX2 is not well understood. Here we present the structure of the human NOX2-p22 complex activated by fragments of three cytosolic factors: p47, p67 and Rac1. The structure reveals that the p67-Rac1 complex clamps onto the dehydrogenase domain of NOX2 and induces its contraction, which stabilizes the binding of NADPH and results in a reduction of the distance between the NADPH-binding domain and the flavin adenine dinucleotide (FAD)-binding domain. Furthermore, the dehydrogenase domain docks onto the bottom of the transmembrane domain of NOX2, which reduces the distance between FAD and the inner haem. These structural rearrangements might facilitate the efficient transfer of electrons between the redox centres in NOX2 and lead to the activation of phagocyte NADPH oxidase.
    DOI:  https://doi.org/10.1038/s41586-024-07056-1
  57. Nat Commun. 2024 Feb 10. 15(1): 1254
    Eco-evolutionary dynamics of gut phageome in wild gibbons (Hoolock tianxing) with seasonal diet variations.
    Shao-Ming Gao, Han-Lan Fei, Qi Li, Li-Ying Lan, Li-Nan Huang, Peng-Fei Fan.
      It has been extensively studied that the gut microbiome provides animals flexibility to adapt to food variability. Yet, how gut phageome responds to diet variation of wild animals remains unexplored. Here, we analyze the eco-evolutionary dynamics of gut phageome in six wild gibbons (Hoolock tianxing) by collecting individually-resolved fresh fecal samples and parallel feeding behavior data for 15 consecutive months. Application of complementary viral and microbial metagenomics recovers 39,198 virulent and temperate phage genomes from the feces. Hierarchical cluster analyses show remarkable seasonal diet variations in gibbons. From high-fruit to high-leaf feeding period, the abundances of phage populations are seasonally fluctuated, especially driven by the increased abundance of virulent phages that kill the Lachnospiraceae hosts, and a decreased abundance of temperate phages that piggyback the Bacteroidaceae hosts. Functional profiling reveals an enrichment through horizontal gene transfers of toxin-antitoxin genes on temperate phage genomes in high-leaf season, potentially conferring benefits to their prokaryotic hosts. The phage-host ecological dynamics are driven by the coevolutionary processes which select for tail fiber and DNA primase genes on virulent and temperate phage genomes, respectively. Our results highlight complex phageome-microbiome interactions as a key feature of the gibbon gut microbial ecosystem responding to the seasonal diet.
    DOI:  https://doi.org/10.1038/s41467-024-45663-8
  58. Immunity. 2024 Feb 13. pii: S1074-7613(24)00028-1. [Epub ahead of print]57(2): 333-348.e6
    A GPCR-neuropeptide axis dampens hyperactive neutrophils by promoting an alternative-like polarization during bacterial infection.
    Naina Gour, Hwan Mee Yong, Aishwarya Magesh, Aishwarya Atakkatan, Felipe Andrade, Stephane Lajoie, Xinzhong Dong.
      The notion that neutrophils exist as a homogeneous population is being replaced with the knowledge that neutrophils adopt different functional states. Neutrophils can have a pro-inflammatory phenotype or an anti-inflammatory state, but how these states are regulated remains unclear. Here, we demonstrated that the neutrophil-expressed G-protein-coupled receptor (GPCR) Mrgpra1 is a negative regulator of neutrophil bactericidal functions. Mrgpra1-mediated signaling was driven by its ligand, neuropeptide FF (NPFF), which dictated the balance between pro- and anti-inflammatory programming. Specifically, the Mrgpra1-NPFF axis counter-regulated interferon (IFN) γ-mediated neutrophil polarization during acute lung infection by favoring an alternative-like polarization, suggesting that it may act to balance overzealous neutrophilic responses. Distinct, cross-regulated populations of neutrophils were the primary source of NPFF and IFNγ during infection. As a subset of neutrophils at steady state expressed NPFF, these findings could have broad implications in various infectious and inflammatory diseases. Therefore, a neutrophil-intrinsic pathway determines their cellular fate, function, and magnitude of infection.
    Keywords:  IFNγ; Mrgpra1 GPCR; NPFF; lung infection; neuropeptide FF; neutrophil polarization; neutrophils
    DOI:  https://doi.org/10.1016/j.immuni.2024.01.003
  59. Nat Commun. 2024 Feb 10. 15(1): 1250
    Structural role for DNA Ligase IV in promoting the fidelity of non-homologous end joining.
    Benjamin M Stinson, Sean M Carney, Johannes C Walter, Joseph J Loparo.
      Nonhomologous end joining (NHEJ), the primary pathway of vertebrate DNA double-strand-break (DSB) repair, directly re-ligates broken DNA ends. Damaged DSB ends that cannot be immediately re-ligated are modified by NHEJ processing enzymes, including error-prone polymerases and nucleases, to enable ligation. However, DSB ends that are initially compatible for re-ligation are typically joined without end processing. As both ligation and end processing occur in the short-range (SR) synaptic complex that closely aligns DNA ends, it remains unclear how ligation of compatible ends is prioritized over end processing. In this study, we identify structural interactions of the NHEJ-specific DNA Ligase IV (Lig4) within the SR complex that prioritize ligation and promote NHEJ fidelity. Mutational analysis demonstrates that Lig4 must bind DNA ends to form the SR complex. Furthermore, single-molecule experiments show that a single Lig4 binds both DNA ends at the instant of SR synapsis. Thus, Lig4 is poised to ligate compatible ends upon initial formation of the SR complex before error-prone processing. Our results provide a molecular basis for the fidelity of NHEJ.
    DOI:  https://doi.org/10.1038/s41467-024-45553-z
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