Virus-induced autophagic degradation of STAT2 as a mechanism for interferon signaling blockade
Virus-induced autophagic degradation of STAT2 as a mechanism for interferon signaling blockade
复制标题
DOI：
10.15252/embr.201948766
复制
发表时间：
2019-10-11
期刊：
影响因子：
7.7
通讯作者：
Sevilla, Noemi
中科院分区：
文献类型：
--
作者：
Avia, Miguel;Rojas, Jose M.;Sevilla, Noemi
哺乳动物干扰素（IFN）信号传导途径是先天性抗病毒应答的主要组成部分，并且病毒病原体已经进化出多种机制来拮抗该途径并促进感染。蓝舌病病毒（BTV）是呼肠孤病毒科（Reoviridae）的一种环状病毒，由蠓传播给反刍动物，引起的疾病造成重大经济损失并限制动物贸易，是世界动物卫生组织（OIE）的强制性通报。在这里，我们表明，BTV干扰IFN-I和IFN-II的反应在两个方面，通过阻断STAT 1磷酸化和降解STAT 2。BTV-NS 3蛋白参与病毒体的排出，与STAT 2相互作用，并通过自噬依赖机制诱导其降解。这种STAT 2降解过程需要E3-Ub-连接酶募集到NS 3以及NS 3 K63多聚泛素化。总之，我们的研究确定了一种新的机制，通过这种机制，病毒降解STAT 2阻断IFN信号，突出了病毒破坏IFN反应的机制的多样性。
The mammalian interferon (IFN) signaling pathway is a primary component of the innate antiviral response, and viral pathogens have evolved multiple mechanisms to antagonize this pathway and to facilitate infection. Bluetongue virus (BTV), an orbivirus of the Reoviridae family, is transmitted by midges to ruminants and causes a disease that produces important economic losses and restriction to animal trade and is of compulsory notification to the World Organization for Animal Health (OIE). Here, we show that BTV interferes with IFN-I and IFN-II responses in two ways, by blocking STAT1 phosphorylation and by degrading STAT2. BTV-NS3 protein, which is involved in virion egress, interacts with STAT2, and induces its degradation by an autophagy-dependent mechanism. This STAT2 degradative process requires the recruitment of an E3-Ub-ligase to NS3 as well as NS3 K63 polyubiquitination. Taken together, our study identifies a new mechanism by which a virus degrades STAT2 for IFN signaling blockade, highlighting the diversity of mechanisms employed by viruses to subvert the IFN response.