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Juan Du, Dawei Zhang, Wei Zhang, Gang Ouyang, Jing Wang, Xing Liu, Shun Li, Wei Ji, Wei Liu, Wuhan Xiao, pVHL Negatively Regulates Antiviral Signaling by Targeting MAVS for Proteasomal Degradation, The Journal of Immunology, Volume 195, Issue 4, August 2015, Pages 1782–1790, https://doi.org/10.4049/jimmunol.1500588
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Abstract
The von Hippel–Lindau (VHL) gene is a well-defined tumor suppressor linked to human heredity cancer syndromes. As a component of the VHL-elongin B/C E3 ligase complex, pVHL performs its tumor function by targeting proteins for proteasomal degradation. It is largely unknown whether pVHL functions in antiviral immunity. In this article, we identify that pVHL negatively regulates innate antiviral immunity, which acts mainly by inducing degradation of mitochondrial antiviral-signaling protein (MAVS, also known as Cardif, IPS-1, or VISA). Overexpression of pVHL abrogated the cellular response to viral infection, whereas knockdown of pVHL exerted the opposite effect. pVHL targeted the K420 residue of MAVS to catalyze the formation of K48-linked polyubiquitin chains, leading to proteasomal degradation of MAVS. After viral infection, Mavs levels remained low in wild type zebrafish embryos but became much higher in vhl-deficient (vhl−/−) zebrafish embryos. Higher MAVS levels correlated with a greatly exaggerated antiviral response. In this work, we demonstrate that pVHL exhibits a previously unknown role in innate antiviral immunity.