Rotavirus VP3 targets MAVS for degradation to inhibit type III interferon expression in intestinal epithelial cells.
Rotavirus VP3 targets MAVS for degradation to inhibit type III interferon expression in intestinal epithelial cells.
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DOI：
10.7554/elife.39494
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发表时间：
2018-11-21
期刊：
影响因子：
7.7
通讯作者：
Greenberg HB
中科院分区：
文献类型：
--
作者：
Ding S;Zhu S;Ren L;Feng N;Song Y;Ge X;Li B;Flavell RA;Greenberg HB
轮状病毒(RV)是引起婴幼儿和许多哺乳动物严重腹泻的主要原因，已进化出多种策略来对抗宿主的先天免疫，特别是通过轮状病毒非结构蛋白1(NSP1)传递的干扰素(IFN)信号。然而，轮状病毒结构成分是否也颠覆抗病毒反应仍处于研究阶段。在这里，我们发现在干扰素诱导的上游对宿主RNA传感途径至关重要的MAV被RV RNA甲基和鸟苷酸转移酶(VP3)以宿主范围受限的方式降解。在机制上，VP3定位于线粒体，并介导MAVS富含Pro区域中一个先前未知的SPLTSS基序的磷酸化，导致其蛋白酶体降解和阻断RV感染的肠上皮细胞中干扰素-λ的产生。重要的是，VP3对MAVS活性的抑制有助于促进轮状病毒的复制和体内病毒的致病。总之，我们的发现证实轮状病毒VP3是哺乳动物MAVS功能的病毒拮抗剂，并揭示了一种新的病原体介导的MAVS信号抑制机制。
Rotaviruses (RVs), a leading cause of severe diarrhea in young children and many mammalian species, have evolved multiple strategies to counteract the host innate immunity, specifically interferon (IFN) signaling through RV non-structural protein 1 (NSP1). However, whether RV structural components also subvert antiviral response remains under-studied. Here, we found that MAVS, critical for the host RNA sensing pathway upstream of IFN induction, is degraded by the RV RNA methyl- and guanylyl-transferase (VP3) in a host-range-restricted manner. Mechanistically, VP3 localizes to the mitochondria and mediates the phosphorylation of a previously unidentified SPLTSS motif within the MAVS proline-rich region, leading to its proteasomal degradation and blockade of IFN-λ production in RV-infected intestinal epithelial cells. Importantly, VP3 inhibition of MAVS activity contributes to enhanced RV replication and to viral pathogenesis in vivo. Collectively, our findings establish RV VP3 as a viral antagonist of MAVS function in mammals and uncover a novel pathogen-mediated inhibitory mechanism of MAVS signaling.