A class of viral inducer of degradation of the necroptosis adaptor RIPK3 regulates virus-induced inflammation.
A class of viral inducer of degradation of the necroptosis adaptor RIPK3 regulates virus-induced inflammation.
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DOI：
10.1016/j.immuni.2020.11.020
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发表时间：
2021-02-09
期刊：
影响因子：
32.4
通讯作者：
Chan FK
中科院分区：
文献类型：
--
作者：
Liu Z;Nailwal H;Rector J;Rahman MM;Sam R;McFadden G;Chan FK
针对天花的疫苗株，痘苗病毒(VACV)，具有高度的免疫原性，但会导致相对良性的疾病。这些特征被认为是由VACV中的基因丢失引起的。利用靶向siRNA筛选，我们鉴定了在牛痘病毒(CPXV)和其他正痘病毒中发现的一种病毒抑制物，该病毒抑制物与宿主Skp1-Cullin1-F-box(SCF)机制和必需的坏死下垂蛋白受体相互作用蛋白Kinase3(RIPK3)结合。这种“RIPK3降解病毒诱导剂(VIRD)”引发了泛素化和蛋白酶体介导的RIPK3降解，并抑制了坏死性下垂。与正痘病毒不同的是，感染RIPK3缺陷宿主的远亲麻痘病毒粘瘤病毒(MYXV)缺乏功能上的vIRD。将vIRD引入VACV，编码截短和有缺陷的vIRD，增强了小鼠的病毒复制。缺失vIRD可以减少CPXV诱导的炎症、病毒复制和死亡率，这在RIPK3和MLKL缺陷小鼠中是相反的。因此，vIRD-RIPK3驱动病原体-宿主的进化，并调节病毒诱导的炎症和发病机制。正痘病毒痘苗病毒使细胞对肿瘤坏死因子诱导的坏死性下垂敏感，但尚不清楚其他正痘病毒是否也使细胞对坏死性下垂敏感。刘等人。证明了一系列以RIPK3为靶点的正痘病毒病毒抑制剂可降解蛋白酶体。这一策略对病毒复制和抗病毒先天免疫起着至关重要的控制作用。
The vaccine strain against smallpox, vaccinia virus (VACV), is highly immunogenic yet causes relatively benign disease. These attributes are believed to be caused by gene loss in VACV. Using a targeted siRNA screen, we identified a viral inhibitor found in cowpox virus (CPXV) and other orthopoxviruses that bound to the host SKP1-Cullin1-F-box (SCF) machinery and the essential necroptosis kinase Receptor Interacting Protein Kinase 3 (RIPK3). This “viral inducer of RIPK3 degradation (vIRD)” triggered ubiquitination and proteasome-mediated degradation of RIPK3 and inhibited necroptosis. In contrast to orthopoxviruses, the distantly related leporipoxvirus Myxoma virus (MYXV), which infects RIPK3-deficient hosts, lacks a functional vIRD. Introduction of vIRD into VACV, which encodes a truncated and defective vIRD, enhanced viral replication in mice. Deletion of vIRD reduced CPXV-induced inflammation, viral replication and mortality, which were reversed in RIPK3- and MLKL-deficient mice. Hence, vIRD-RIPK3 drives pathogen-host evolution and regulates virus-induced inflammation and pathogenesis. The orthopoxvirus vaccinia virus sensitizes cells to TNF-induced necroptosis, but it is not known whether other orthopoxviruses also sensitizes cells to necroptosis. Liu et al. demonstrate that a family of orthopoxvirus viral inhibitors that targets RIPK3 for proteasomal degradation. This strategy critically controls viral replication and anti-viral innate immunity.
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影响因子：
--
作者：
Moriwaki K;Chan FK
通讯作者：
Chan FK
影响因子：
15.3
作者：
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