N6-methyladenosine RNA modification suppresses antiviral innate sensing pathways via reshaping double-stranded RNA

Nature Communications, Год журнала: 2021, Номер 12(1)

Опубликована: Март 11, 2021

Abstract Double-stranded RNA (dsRNA) is a virus-encoded signature capable of triggering intracellular Rig-like receptors (RLR) to activate antiviral signaling, but whether intercellular dsRNA structural reshaping mediated by the N 6 -methyladenosine (m A) modification modulates this process remains largely unknown. Here, we show that, in response infection virus Vesicular Stomatitis Virus (VSV), m A methyltransferase METTL3 translocates into cytoplasm increase on virus-derived transcripts and decrease viral formation, thereby reducing virus-sensing efficacy RLRs such as RIG-I MDA5 dampening immune signaling. Meanwhile, genetic ablation monocyte or hepatocyte causes enhanced type I IFN expression accelerates VSV clearance. Our findings thus implicate METTL3-mediated RNAs negative regulator for innate sensing pathways dsRNA, also hint potential therapeutic target modulation anti-viral immunity.

Язык: Английский

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Cell Cycle Checkpoints Cooperate to Suppress DNA- and RNA-Associated Molecular Pattern Recognition and Anti-Tumor Immune Responses

Cell Reports, Год журнала: 2020, Номер 32(9), С. 108080 - 108080

Опубликована: Сен. 1, 2020

The DNA-dependent pattern recognition receptor, cGAS (cyclic GMP-AMP synthase), mediates communication between the DNA damage and immune responses. Mitotic chromosome missegregation stimulates activity; however, it is unclear whether progression through mitosis required for cancercell-intrinsic activation of anti-tumor Moreover, unknown cell cycle checkpoint disruption can restore responses in cancer cells that are recalcitrant to DNAdamage-induced inflammation. Here, we demonstrate prolonged arrest at G2-mitosis boundary from either excessive or CDK1 inhibition prevents inflammatory-stimulated gene expression immune-mediated destruction distal tumors. Remarkably, inflammatory signaling restored a RIG-I-dependent manner upon concomitant p53 G2 checkpoint. These findings link aberrant loss an expanded spectrum damage-associated molecular have implications design rational approaches augment

Язык: Английский

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A novel selective autophagy receptor, CCDC50, delivers K63 polyubiquitination-activated RIG-I/MDA5 for degradation during viral infection

Cell Research, Год журнала: 2020, Номер 31(1), С. 62 - 79

Опубликована: Июль 1, 2020

Язык: Английский

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Identification of poly(ADP-ribose) polymerase 9 (PARP9) as a noncanonical sensor for RNA virus in dendritic cells

Nature Communications, Год журнала: 2021, Номер 12(1)

Опубликована: Май 11, 2021

Abstract Innate immune cells are critical in protective immunity against viral infections, involved sensing foreign nucleic acids. Here we report that the poly(ADP-ribose) polymerase 9 (PARP9), a member of PARP family, serves as non-canonical sensor for RNA virus to initiate and amplify type I interferon (IFN) production. We find knockdown or deletion PARP9 human mouse dendritic macrophages inhibits IFN production response double strand stimulation infection. Furthermore, mice deficient show enhanced susceptibility infections with viruses because impaired Mechanistically, recognizes binds RNA, resultant recruitment activation phosphoinositide 3-kinase (PI3K) AKT3 pathway, independent mitochondrial antiviral-signaling (MAVS). PI3K/AKT3 then activates IRF3 IRF7 by phosphorylating at Ser385 Ser437/438 mediating Together, reveal role depends on pathway produce IFN. These findings may have important clinical implications controlling viral-induced diseases targeting PARP9.

Язык: Английский

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Human enteric viruses autonomously shape inflammatory bowel disease phenotype through divergent innate immunomodulation

Science Immunology, Год журнала: 2022, Номер 7(70)

Опубликована: Апрель 8, 2022

Altered enteric microorganisms in concert with host genetics shape inflammatory bowel disease (IBD) phenotypes. However, insight is limited to bacteria and fungi. We found that eukaryotic viruses bacteriophages (collectively, the virome), enriched from non-IBD, noninflamed human colon resections, actively elicited atypical anti-inflammatory innate immune programs. Conversely, ulcerative colitis or Crohn's resection viromes provoked inflammation, which was successfully dampened by non-IBD viromes. The IBD tissue virome perturbed, including an increase enterovirus B species of picornaviruses, not previously detected fecal studies. Mice humanized were protected intestinal whereas mice exhibited exacerbated inflammation a nucleic acid sensing-dependent fashion. Furthermore, there detrimental consequences for patient-derived epithelial cells bearing loss-of-function mutations within virus sensor MDA5 when exposed Our results demonstrate recognition autonomously influences homeostasis Thus, perturbations virome, altered ability sense due genetic variation, contribute induction IBD. Harnessing may offer therapeutic biomarker potential.

Язык: Английский

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