Liu GuanQun, Lee Jung-Hyun, Parker Zachary M, Acharya Dhiraj, Chiang Jessica J, van Gent Michiel, Riedl William, Davis-Gardner Meredith E, Wies Effi, Chiang Cindy, Gack Michaela U
Florida Research and Innovation Center, Cleveland Clinic, FL 34987, USA.
Department of Microbiology, The University of Chicago, Chicago, IL 60637, USA.
bioRxiv. 2020 Oct 27:2020.10.26.356048. doi: 10.1101/2020.10.26.356048.
Activation of the RIG-I-like receptors, RIG-I and MDA5, establishes an antiviral state by upregulating interferon (IFN)-stimulated genes (ISGs). Among these is ISG15 whose mechanistic roles in innate immunity still remain enigmatic. Here we report that ISGylation is essential for antiviral IFN responses mediated by the viral RNA sensor MDA5. ISG15 conjugation to the caspase activation and recruitment domains of MDA5 promotes the formation of higher-order assemblies of MDA5 and thereby triggers activation of innate immunity against a range of viruses including coronaviruses, flaviviruses and picornaviruses. The ISG15-dependent activation of MDA5 is antagonized through direct de-ISGylation mediated by the papain-like protease (PLpro) of SARS-CoV-2, a recently emerged coronavirus that causes the COVID-19 pandemic. Our work demonstrates a crucial role for ISG15 in the MDA5-mediated antiviral response, and also identifies a novel immune evasion mechanism of SARS-CoV-2, which may be targeted for the development of new antivirals and vaccines to combat COVID-19.
维甲酸诱导基因I样受体（RIG-I）和黑色素瘤分化相关基因5（MDA5）的激活通过上调干扰素（IFN）刺激基因（ISG）建立抗病毒状态。其中包括ISG15，其在先天免疫中的作用机制仍不清楚。在此，我们报告ISGylation对于病毒RNA传感器MDA5介导的抗病毒IFN反应至关重要。ISG15与MDA5的半胱天冬酶激活和募集结构域结合，促进MDA5高阶组装体的形成，从而触发针对包括冠状病毒、黄病毒和小RNA病毒在内的一系列病毒的先天免疫激活。由最近出现的导致COVID-19大流行的冠状病毒SARS-CoV-2的木瓜样蛋白酶（PLpro）介导的直接去ISGylation作用，拮抗了ISG15依赖的MDA5激活。我们的工作证明了ISG15在MDA5介导的抗病毒反应中的关键作用，并且还确定了SARS-CoV-2一种新的免疫逃逸机制，这可能成为开发对抗COVID-19的新抗病毒药物和疫苗的靶点。
