Choi Young Bong, Shembade Noula, Parvatiyar Kislay, Balachandran Siddharth, Harhaj Edward William
Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, Maryland, USA
Department of Microbiology and Immunology, Sylvester Comprehensive Cancer Center, The University of Miami, Miller School of Medicine, Miami, Florida, USA.
Mol Cell Biol. 2016 Dec 19;37(1). doi: 10.1128/MCB.00422-16. Print 2017 Jan 1.
The host response to RNA virus infection consists of an intrinsic innate immune response and the induction of apoptosis as mechanisms to restrict viral replication. The mitochondrial adaptor molecule MAVS plays critical roles in coordinating both virus-induced type I interferon production and apoptosis; however, the regulation of MAVS-mediated apoptosis is poorly understood. Here, we show that the adaptor protein TAX1BP1 functions as a negative regulator of virus-induced apoptosis. TAX1BP1-deficient cells are highly sensitive to apoptosis in response to infection with the RNA viruses vesicular stomatitis virus and Sendai virus and to transfection with poly(I·C). TAX1BP1 undergoes degradation during RNA virus infection, and loss of TAX1BP1 is associated with apoptotic cell death. TAX1BP1 deficiency augments virus-induced activation of proapoptotic c-Jun N-terminal kinase (JNK) signaling. Virus infection promotes the mitochondrial localization of TAX1BP1 and concomitant interaction with the mitochondrial adaptor MAVS. TAX1BP1 recruits the E3 ligase Itch to MAVS to trigger its ubiquitination and degradation, and loss of TAX1BP1 or Itch results in increased MAVS protein expression. Together, these results indicate that TAX1BP1 functions as an adaptor molecule for Itch to target MAVS during RNA virus infection and thus restrict virus-induced apoptosis.
宿主对RNA病毒感染的反应包括内在的先天免疫反应和诱导细胞凋亡，以此作为限制病毒复制的机制。线粒体衔接分子MAVS在协调病毒诱导的I型干扰素产生和细胞凋亡过程中发挥关键作用；然而，对MAVS介导的细胞凋亡的调控却知之甚少。在此，我们表明衔接蛋白TAX1BP1作为病毒诱导的细胞凋亡的负调节因子发挥作用。TAX1BP1缺陷型细胞对RNA病毒水疱性口炎病毒和仙台病毒感染以及聚肌苷酸-聚胞苷酸（poly(I·C)）转染诱导的细胞凋亡高度敏感。在RNA病毒感染期间，TAX1BP1会发生降解，而TAX1BP1的缺失与凋亡性细胞死亡相关。TAX1BP1缺陷会增强病毒诱导的促凋亡c-Jun氨基末端激酶（JNK）信号通路的激活。病毒感染促进TAX1BP1定位于线粒体，并与线粒体衔接分子MAVS发生相互作用。TAX1BP1招募E3泛素连接酶Itch至MAVS，以触发其泛素化和降解，而TAX1BP1或Itch的缺失会导致MAVS蛋白表达增加。总之，这些结果表明，在RNA病毒感染期间，TAX1BP1作为Itch的衔接分子靶向MAVS，从而限制病毒诱导的细胞凋亡。
