小柯机器人

美国杜克大学医学院Francis Ka-Ming Chan课题组取得最新进展。他们发现细胞坏死适配器RIPK3降解的一类病毒诱导物调节病毒诱导的炎症。2021年1月13日出版的《免疫》杂志发表了这项成果。

使用针对性的小干扰RNA（siRNA）筛选，他们发现了在牛痘病毒（CPXV）和其他正痘病毒中发现的病毒抑制剂，该病毒抑制剂与宿主SKP1-Cullin1-F-box（SCF）机器以及必需的坏死性激酶受体相互作用蛋白激酶3（RIPK3）相结合。这种“ RIPK3降解的病毒诱导剂”（vIRD）引发了泛素化和蛋白酶体介导的RIPK3降解，并抑制细胞坏死。

与正痘病毒相反，感染RIPK3缺陷宿主的远缘性猪痘病毒粘液瘤病毒（MYXV）缺少功能性vIRD。将vIRD引入抗天花痘苗病毒（VACV）中，该VACV编码截短且有缺陷的vIRD，可增强小鼠中的病毒复制。vIRD的敲除减少了CPXV诱导的炎症、病毒复制和死亡率，这在RIPK3和MLKL缺陷小鼠中被逆转。因此，vIRD-RIPK3驱动病原体宿主进化并调节病毒诱导的炎症和发病机理。

据悉，VACV的疫苗株具有高免疫原性，但会引起相对良性的疾病。这些属性被认为是由VACV基因丢失引起的。

附：英文原文

Title: A class of viral inducer of degradation of the necroptosis adaptor RIPK3 regulates virus-induced inflammation

Author: Zhijun Liu, Himani Nailwal, Jonah Rector, Masmudur M. Rahman, Richard Sam, Grant McFadden, Francis Ka-Ming Chan

Issue&Volume: 2021-01-13

Abstract: The vaccine strain against smallpox, vaccinia virus (VACV), is highly immunogenicyet causes relatively benign disease. These attributes are believed to be caused bygene loss in VACV. Using a targeted small interfering RNA (siRNA) screen, we identifieda viral inhibitor found in cowpox virus (CPXV) and other orthopoxviruses that boundto the host SKP1-Cullin1-F-box (SCF) machinery and the essential necroptosis kinasereceptor interacting protein kinase 3 (RIPK3). This “viral inducer of RIPK3 degradation”(vIRD) triggered ubiquitination and proteasome-mediated degradation of RIPK3 and inhibitednecroptosis. In contrast to orthopoxviruses, the distantly related leporipoxvirusmyxoma virus (MYXV), which infects RIPK3-deficient hosts, lacks a functional vIRD.Introduction of vIRD into VACV, which encodes a truncated and defective vIRD, enhancedviral replication in mice. Deletion of vIRD reduced CPXV-induced inflammation, viralreplication, and mortality, which were reversed in RIPK3- and MLKL-deficient mice.Hence, vIRD-RIPK3 drives pathogen-host evolution and regulates virus-induced inflammationand pathogenesis.

DOI: 10.1016/j.immuni.2020.11.020

Source: https://www.cell.com/immunity/fulltext/S1074-7613(20)30507-0

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