pVHL Negatively Regulates Antiviral Signaling by Targeting MAVS for Proteasomal Degradation

Du J, Zhang D, Zhang W, Ouyang G, Wang J, Liu X, Li S, Ji W, Liu W, Xiao W.

The Journal of Immunology (2015) 195:1782-1790.

Speaker: Wei-Sheng Chen (陳維昇)         Time: 14:10~15:00, March. 30, 2016

Commentator: Dr. Pin Ling (凌斌 老師)     Place: Room 601

Abstract:

The von Hippel–Lindau (VHL) gene is a well-known tumor suppressor that is linked to human heredity cancer syndromes (1). The protein encoded by VHL (pVHL) forms a ternary complex, namely VHL-elongin B/C (VCB) complex, containing ubiquitin ligase activities targeting the proline hydroxylated hypoxia-induced factor (HIF)-1/2a for proteasomal degradation under normoxia conditions (2). However, the mechanisms and consequences of pVHL-induced ubiquitination of non–HIF-1/2a targets still await. In this study, the authors linked pVHL to the antiviral responses by showing that pVHL negatively regulated mitochondrial antiviral signaling protein (MAVS) mediated signaling. The MAVS is an adaptor protein of retinoic acid-inducible gene (RIG-I)-like receptors (RLRs) which could lead to the production of type I IFNs and proinflammatory cytokines upon viral infection (3). The authors found that pVHL interacts with MAVS and conjugates a polyubiquitin chain at the K420 residue of MAVS. Consistently, overexpression of pVHL aborgated IFN promoter activation upon the infection of RNA viruses, while knockdown of pVHL had opposite effects. Additionally, using the TALEN technique, the authors generated two zebrafish lines with mutated vhl. The pVHL homolog in zebrafish embryos shows similar phenomena to mammalian pVHL: pVHL is resoponsible for mediating protein level of endogenous MAVS and the antiviral response in zebrafish could be negatively regulated through pVHL-mediated MAVS degradation. In summary, this study reveals a novel target of pVHL and thus provides new insights in the physiological functions of pVHL.

References:

1.     Gossage L, Eisen T, Maher ER. 2015. VHL, the story of a tumour suppressor gene. Nat Rev Cancer 15:55-64.

2.     Shen C, Kaelin WG. 2013. The VHL/HIF Axis in Clear Cell Renal Carcinoma. Seminars in cancer biology 23:18-25.

3.     Sun Q, Sun L, Liu H-H, Chen X, Seth RB, Forman J, Chen ZJ. 2006. The Specific and Essential Role of MAVS in Antiviral Innate Immune Responses. Immunity 24:633-642.