PDF(Pubmed)
Abstract：
Cysteine palmitoylation or S-palmitoylation catalyzed by the ZDHHC family of acyltransferases regulates the biological function of numerous mammalian proteins as well as viral proteins. However, understanding of the role of S-palmitoylation in antiviral immunity against RNA viruses remains very limited. The adaptor protein MAVS forms functionally essential prion-like aggregates upon activation by viral RNA-sensing RIG-I-like receptors. Here, we identify that MAVS, a C-terminal tail-anchored mitochondrial outer membrane protein, is S-palmitoylated by ZDHHC7 at Cys508, a residue adjacent to the tail-anchor transmembrane helix. Using superresolution microscopy and other biochemical techniques, we found that the mitochondrial localization of MAVS at resting state mainly depends on its transmembrane tail-anchor, without regulation by Cys508 S-palmitoylation. However, upon viral infection, MAVS S-palmitoylation stabilizes its aggregation on the mitochondrial outer membrane and thus promotes subsequent propagation of antiviral signaling. We further show that inhibition of MAVS S-palmitoylation increases the host susceptibility to RNA virus infection, highlighting the importance of S-palmitoylation in the antiviral innate immunity. Also, our results indicate ZDHHC7 as a potential therapeutic target for MAVS-related autoimmune diseases.
摘要：
由ZDHHC系列酰基转移酶催化的半胱氨酸棕榈酰化或S-棕榈酰化调节许多哺乳动物蛋白质以及病毒蛋白质的生物学功能。然而,对S-棕榈酰化在针对RNA病毒的抗病毒免疫中的作用的理解仍然非常有限.衔接蛋白MAVS在被病毒RNA敏感RIG-I样受体激活后形成功能必需的朊病毒样聚集体。这里,我们确定MAVS，C端尾部锚定的线粒体外膜蛋白，在Cys508(与尾锚跨膜螺旋相邻的残基)处被ZDHHC7S-棕榈酰化。使用超分辨率显微镜和其他生化技术，我们发现MAVS在静息状态下的线粒体定位主要取决于其跨膜尾锚,不受Cys508S-棕榈酰化调节。然而,病毒感染后，MAVS-棕榈酰化稳定其在线粒体外膜上的聚集，从而促进抗病毒信号的后续传播。我们进一步表明，抑制MAVSS-棕榈酰化增加了宿主对RNA病毒感染的易感性，强调S-棕榈酰化在抗病毒先天免疫中的重要性。此外，我们的结果表明ZDHHC7是MAVS相关自身免疫性疾病的潜在治疗靶点.
