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OASL 相分离诱导 RIPK3 形成淀粉样纤维，从而促进病毒诱导的细胞坏死。

OASL phase condensation induces amyloid-like fibrillation of RIPK3 to promote virus-induced necroptosis.

机构信息

Department of Cancer Biology, Infection Biology Program, and Global Center for Pathogen Research and Human Health, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.

Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.

出版信息

Nat Cell Biol. 2023 Jan;25(1):92-107. doi: 10.1038/s41556-022-01039-y. Epub 2023 Jan 5.

DOI:10.1038/s41556-022-01039-y
PMID:36604592
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9859756/
Abstract

RIPK3-ZBP1-MLKL-mediated necroptosis is a proinflammatory cell death process that is crucial for antiviral host defence. RIPK3 self-oligomerization and autophosphorylation are prerequisites for executing necroptosis, yet the underlying mechanism of virus-induced RIPK3 activation remains elusive. Interferon-inducible 2'-5' oligoadenylate synthetase-like (OASL) protein is devoid of enzymatic function but displays potent antiviral activity. Here we describe a role of OASL as a virus-induced necroptosis promoter that scaffolds the RIPK3-ZBP1 non-canonical necrosome via liquid-like phase condensation. This liquid-like platform of OASL recruits RIPK3 and ZBP1 via protein-protein interactions to provide spatial segregation for RIPK3 nucleation. This process facilitates the amyloid-like fibril formation and activation of RIPK3 and thereby MLKL phosphorylation for necroptosis. Mice deficient in Oasl1 exhibit severely impaired necroptosis and attenuated inflammation after viral infection, resulting in uncontrolled viral dissemination and lethality. Our study demonstrates an interferon-induced innate response whereby OASL scaffolds RIPK3-ZBP1 assembly via its phase-separated liquid droplets to facilitate necroptosis-mediated antiviral immunity.

摘要

RIPK3-ZBP1-MLKL 介导的坏死性细胞凋亡是一种促炎细胞死亡过程，对抗病毒宿主防御至关重要。RIPK3 自身寡聚化和自磷酸化是执行坏死性细胞凋亡的前提条件，然而病毒诱导的 RIPK3 激活的潜在机制仍然难以捉摸。干扰素诱导的 2'-5'寡聚腺苷酸合成酶样（OASL）蛋白缺乏酶活性，但具有很强的抗病毒活性。在这里，我们描述了 OASL 作为一种病毒诱导的坏死性细胞凋亡促进剂的作用，它通过液-液相分离来支架 RIPK3-ZBP1 非经典坏死小体。这种 OASL 的液相平台通过蛋白-蛋白相互作用招募 RIPK3 和 ZBP1，为 RIPK3 成核提供空间隔离。这个过程促进了 RIPK3 的淀粉样纤维形成和激活，从而导致 MLKL 磷酸化引发坏死性细胞凋亡。缺乏 Oasl1 的小鼠在病毒感染后表现出严重的坏死性细胞凋亡缺陷和炎症反应减弱，导致病毒无法控制地传播和致命性。我们的研究表明，一种干扰素诱导的先天反应，其中 OASL 通过其相分离的液滴来支架 RIPK3-ZBP1 组装，从而促进坏死性细胞凋亡介导的抗病毒免疫。

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