Department of Immunology, University of Washington School of Medicine, Seattle, WA 98195, USA.
Proc Natl Acad Sci U S A. 2011 Aug 30;108(35):14590-5. doi: 10.1073/pnas.1110133108. Epub 2011 Aug 15.
RIG-I is a cytosolic pathogen recognition receptor that engages viral RNA in infected cells to trigger innate immune defenses through its adaptor protein MAVS. MAVS resides on mitochondria and peroxisomes, but how its signaling is coordinated among these organelles has not been defined. Here we show that a major site of MAVS signaling is the mitochondrial-associated membrane (MAM), a distinct membrane compartment that links the endoplasmic reticulum to mitochondria. During RNA virus infection, RIG-I is recruited to the MAM to bind MAVS. Dynamic MAM tethering to mitochondria and peroxisomes then coordinates MAVS localization to form a signaling synapse between membranes. Importantly, the hepatitis C virus NS3/4A protease, which cleaves MAVS to support persistent infection, targets this synapse for MAVS proteolysis from the MAM, but not from mitochondria, to ablate RIG-I signaling of immune defenses. Thus, the MAM mediates an intracellular immune synapse that directs antiviral innate immunity.
RIG-I 是一种胞质病原体识别受体，它在感染细胞中与病毒 RNA 结合，通过其衔接蛋白 MAVS 触发先天免疫防御。MAVS 位于线粒体和过氧化物酶体上，但它的信号如何在这些细胞器之间协调尚未确定。在这里，我们表明 MAVS 信号的主要部位是线粒体相关膜（MAM），这是一种将内质网与线粒体连接起来的独特膜隔室。在 RNA 病毒感染期间，RIG-I 被招募到 MAM 以结合 MAVS。然后，动态的 MAM 与线粒体和过氧化物酶体的连接将协调 MAVS 的定位，在膜之间形成信号突触。重要的是，丙型肝炎病毒 NS3/4A 蛋白酶切割 MAVS 以支持持续性感染，它将这个突触作为 MAVS 从 MAM 而不是线粒体的蛋白水解的靶点，从而消除 RIG-I 信号对免疫防御的作用。因此，MAM 介导了一个细胞内免疫突触，指导抗病毒先天免疫。
