Hepatitis B Virus-Induced Parkin-Dependent Recruitment of Linear Ubiquitin Assembly Complex (LUBAC) to Mitochondria and Attenuation of Innate Immunity

Abstract

Hepatitis B virus (HBV) suppresses innate immune signaling to establish persistent infection. Although HBV is a DNA virus, its pre-genomic RNA (pgRNA) can be sensed by RIG-I and activates MAVS to mediate interferon (IFN) λ synthesis. Despite of the activation of RIG-I-MAVS axis by pgRNA, the underlying mechanism explaining how HBV infection fails to induce interferon-αβ (IFN) synthesis remained uncharacterized. We demonstrate that HBV induced parkin is able to recruit the linear ubiquitin assembly complex (LUBAC) to mitochondria and abrogates IFN β synthesis. Parkin interacts with MAVS, accumulates unanchored linear polyubiquitin chains on MAVS via LUBAC, to disrupt MAVS signalosome and attenuate IRF3 activation. This study highlights the novel role of parkin in antiviral signaling which involves LUBAC being recruited to the mitochondria. These results provide avenues of investigations on the role of mitochondrial dynamics in innate immunity.

Author Summary

Hepatitis B virus (HBV) chronic infection is one of the major causes of hepatocellular carcinoma. HBV infection is associated with mitochondrial dysfunction. We previously showed that persistent infection of HBV requires rapid clearance of impaired mitochondria by mitophagy, a cellular quality control process that insures survival of HBV infected cells. During the process, Parkin, an RBR E3 ligase, is recruited to mitochondria to induce mitophagy. In this study, we show that the Parkin, plays a critical role in the modulation of innate immune signaling. Using HBV expressing cells, we show that the Parkin recruits linear ubiquitin assembly complex (LUBAC) to the mitochondria and subsequently inhibits downstream signaling of mitochondrial antiviral signaling protein (MAVS). Mitochondrial LUBAC then catalyzes linear ubiquitin chains on MAVS, which abrogates its downstream events such as MAVS-TRAFs interaction and abolishes IRF3 phosphorylation. The results of this study highlight the molecular details explaining how HBV can suppress interferon synthesis implicating a mitophagy-independent role of Parkin. HBV-induced mitochondrial damage serves as the platform for recruitment of Parkin and LUBAC, which together modify MAVS by ubiquitination and cripples its downstream signaling.