Selective STAT protein degradation induced by paramyxoviruses requires both STAT1 and STAT2 but is independent of alpha/beta interferon signal transduction
Selective STAT protein degradation induced by paramyxoviruses requires both STAT1 and STAT2 but is independent of alpha/beta interferon signal transduction
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DOI：
10.1128/jvi.76.9.4190-4198.2002
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发表时间：
2002-05-01
影响因子：
5.4
通讯作者：
Horvath, CA
中科院分区：
文献类型：
--
作者：
Parisien, JP;Lau, JF;Horvath, CA
α/β干扰素（IFN-alpha/β）诱导的STAT信号转导途径导致ISGF 3转录复合物的激活和随后的抗病毒反应是病毒发病机制策略的目标。RNA病毒的副粘病毒科的风疹病毒属的成员已经获得了特异性靶向STAT 1或STAT 2进行蛋白水解降解的能力，作为逃避IFN应答的对策。虽然II型人副流感病毒诱导STAT 2降解，但猿猴病毒5诱导STAT 1降解。已经在一系列IFN信号传导蛋白缺陷的人体细胞系中研究了这些副粘病毒降解STAT蛋白所需的IFN信号传导系统的组分。结果表明，无论是IFN-α/β受体，酪氨酸激酶Jak 1或Tyk 2，也不是ISGF 3 DNA结合亚基，IFN调节因子9（IRF 9），是由任一病毒诱导的STAT蛋白降解所必需的。尽管如此，STAT 1和STAT 2在宿主细胞中都是严格需要的，以建立允许降解的环境，使两种病毒能够靶向其各自的STAT蛋白。互补研究表明，STAT蛋白激活酪氨酸磷酸化和功能性src同源2（SH 2）结构域是在降解能力差的细胞中创造一个允许的STAT降解环境所必需的，但缺失的STAT蛋白的N末端是必不可少的。蛋白质-蛋白质相互作用分析表明，V和STAT蛋白在体外和体内物理相互作用。这些结果构成了支持病毒诱导的、不依赖于IFN的STAT蛋白降解复合物的遗传和生化证据，该复合物至少含有STAT 1和STAT 2。
The alpha/beta interferon (IFN-alpha/beta)-induced STAT signal transduction pathway leading to activation of the ISGF3 transcription complex and subsequent antiviral responses is the target of viral pathogenesis strategies. Members of the Rubulavirus genus of the Paramyxovirus family of RNA viruses have acquired the ability to specifically target either STAT1 or STAT2 for proteolytic degradation as a countermeasure for evading IFN responses. While type II human parainfluenza virus induces STAT2 degradation, simian virus 5 induces STAT1 degradation. The components of the IFN signaling system that are required for STAT protein degradation by these paramyxoviruses have been investigated in a series of human somatic cell lines deficient in IFN signaling proteins. Results indicate that neither the IFN-alpha/beta receptor, the tyrosine kinases Jak1 or Tyk2, nor the ISGF3 DNA-binding subunit, IFN regulatory factor 9 (IRF9), is required for STAT protein degradation induced by either virus. Nonetheless, both STAT1 and STAT2 are strictly required in the host cell to establish a degradation-permissive environment enabling both viruses to target their respective STAT protein. Complementation studies reveal that STAT protein-activating tyrosine phosphorylation and functional src homology 2 (SH2) domains are dispensable for creating a permissive STAT degradation environment in degradation-incompetent cells, but the N terminus of the missing STAT protein is essential. Protein-protein interaction analysis indicates that V and STAT proteins interact physically in vitro and in vivo. These results constitute genetic and biochemical evidence supporting a virus-induced, IFN-independent STAT protein degradation complex that contains at least STAT1 and STAT2.