Yang Yan, Liang Yuqiong, Qu Lin, Chen Zeming, Yi Minkyung, Li Kui, Lemon Stanley M
Center for Hepatitis Research, Institute for Human Infections and Immunity, Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555-1019, USA.
Proc Natl Acad Sci U S A. 2007 Apr 24;104(17):7253-8. doi: 10.1073/pnas.0611506104. Epub 2007 Apr 16.
Mitochondrial antiviral signaling protein (MAVS) is an essential component of virus-activated signaling pathways that induce protective IFN responses. Its localization to the outer mitochondrial membrane suggests an important yet unexplained role for mitochondria in innate immunity. Here, we show that hepatitis A virus (HAV), a hepatotropic picornavirus, ablates type 1 IFN responses by targeting the 3ABC precursor of its 3C(pro) cysteine protease to mitochondria where it colocalizes with and cleaves MAVS, thereby disrupting activation of IRF3 through the MDA5 pathway. The 3ABC cleavage of MAVS requires both the protease activity of 3C(pro) and a transmembrane domain in 3A that directs 3ABC to mitochondria. Lacking this domain, mature 3C(pro) protease is incapable of MAVS proteolysis. HAV thus disrupts host signaling by a mechanism that parallels that of the serine NS3/4A protease of hepatitis C virus, but differs in its use of a stable, catalytically active polyprotein processing intermediate. The unique requirement for mitochondrial localization of 3ABC underscores the importance of mitochondria to host control of virus infections within the liver.
线粒体抗病毒信号蛋白（MAVS）是病毒激活的信号通路的重要组成部分，该信号通路可诱导保护性干扰素反应。它定位于线粒体外膜，这表明线粒体在固有免疫中发挥着重要但尚未得到解释的作用。在此，我们发现甲型肝炎病毒（HAV），一种嗜肝小核糖核酸病毒，通过将其3C蛋白酶（3C(pro)）的3ABC前体靶向线粒体，使其与MAVS共定位并切割MAVS，从而破坏通过MDA5途径的IRF3激活，进而消除1型干扰素反应。MAVS的3ABC切割既需要3C(pro)的蛋白酶活性，也需要3A中的跨膜结构域将3ABC导向线粒体。缺乏该结构域时，成熟的3C(pro)蛋白酶无法进行MAVS的蛋白水解。因此，HAV通过一种与丙型肝炎病毒的丝氨酸NS3/4A蛋白酶类似的机制破坏宿主信号传导，但在使用稳定的、具有催化活性的多蛋白加工中间体方面有所不同。3ABC线粒体定位的独特要求突出了线粒体对肝脏内宿主控制病毒感染的重要性。
