Yang Hui, Winkler Wendy, Wu Xiaopeng
Department of Veterinary Medicine, College of Animal Science, Zhejiang University, Hangzhou, China.
Blood Research Institute, Versiti Wisconsin, Milwaukee, Wisconsin, USA.
J Virol. 2021 May 10;95(11). doi: 10.1128/JVI.00283-21. Epub 2021 Mar 10.
Interferon-stimulated genes (ISGs) create multiple lines of defense against viral infection. Here we show that interferon induced protein 35 (IFI35) inhibits swine (H3N2) influenza virus replication by directly interacting with the viral protein NS1. IFI35 binds more preferentially to the effector domain of NS1 (128-207aa) than to the viral RNA sensor RIG-I. This promotes mutual antagonism between IFI35 and NS1, and frees RIG-I from IFI35-mediated K48-linked ubiquitination and degradation. However, IFI35 does not interact with the NS1 encoded by avian (H7N9) influenza virus, resulting in IFI35 playing an opposite virus enabling role during highly pathogenic H7N9 virus infection. Notably, replacing the 128-207aa region of NS1-H7N9 with the corresponding region of NS1-H3N2 results in the chimeric NS1 acquiring the ability to bind to and mutually antagonize IFI35. IFI35 deficient mice accordingly exhibit more resistance to lethal H7N9 infection than their wild-type control exhibit. Our data uncover a novel mechanism by which IFI35 regulates RIG-I-mediated anti-viral immunity through mutual antagonism with influenza protein NS1.IAV infection poses a global health threat, and is among the most common contagious pathogens to cause severe respiratory infections in humans and animals. ISGs play a key role in host defense against IAV infection. In line with others, we show IFI35-mediated ubiquitination of RIG-I to be involved in innate immunity. Moreover, we define a novel role of IFI35 in regulating the type I IFN pathway during IAV infection. We found that IFI35 regulates RIG-I mediated antiviral signaling by interacting with IAV-NS1. H3N2 NS1, but notably not H7N9 NS1, interacts with IFI35 and efficiently suppresses IFI35-dependent ubiquitination of RIG-I. IFI35 deficiency protected mice from H7N9 virus infection. Therefore, manipulation of the IFI35-NS1 provides a new approach for the development of anti-IAV treatments.
干扰素刺激基因（ISGs）建立了多条抵御病毒感染的防线。在此我们表明，干扰素诱导蛋白35（IFI35）通过直接与病毒蛋白NS1相互作用来抑制猪源（H3N2）流感病毒的复制。IFI35与NS1的效应结构域（128 - 207aa）的结合比与病毒RNA传感器RIG-I的结合更具偏好性。这促进了IFI35与NS1之间的相互拮抗作用，并使RIG-I从IFI35介导的K48连接的泛素化和降解中解脱出来。然而，IFI35不与禽源（H7N9）流感病毒编码的NS1相互作用，导致IFI35在高致病性H7N9病毒感染期间发挥相反的病毒促进作用。值得注意的是，用NS1 - H3N2的相应区域替换NS1 - H7N9的128 - 207aa区域会导致嵌合NS1获得与IFI35结合并相互拮抗的能力。因此，IFI35缺陷型小鼠对致死性H7N9感染的抵抗力比野生型对照小鼠更强。我们的数据揭示了一种新机制，即IFI35通过与流感蛋白NS1的相互拮抗作用来调节RIG-I介导的抗病毒免疫。甲型流感病毒（IAV）感染对全球健康构成威胁，是导致人类和动物严重呼吸道感染的最常见传染性病原体之一。ISGs在宿主抵御IAV感染中起关键作用。与其他人的研究一致，我们表明IFI35介导的RIG-I泛素化参与先天免疫。此外，我们确定了IFI35在IAV感染期间调节I型干扰素途径中的新作用。我们发现IFI35通过与IAV-NS1相互作用来调节RIG-I介导的抗病毒信号传导。H3N2 NS1，但值得注意的是H7N9 NS1不与IFI35相互作用，并有效抑制IFI35依赖的RIG-I泛素化。IFI35缺陷保护小鼠免受H7N9病毒感染。因此，操纵IFI35 - NS1为开发抗IAV治疗提供了一种新方法。
