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.
Highlights
Infection by the human hepatitis B virus (HBV) is a major public health burden associated with about 600,000 deaths annually and 350 million chronic carriers worldwide [1]
We previously showed that persistent infection of Hepatitis B virus (HBV) requires rapid clearance of impaired mitochondria by mitophagy, a cellular quality control process that insures survival of HBV infected cells
We show that the Parkin, plays a critical role in the modulation of innate immune signaling
Summary
Infection by the human hepatitis B virus (HBV) is a major public health burden associated with about 600,000 deaths annually and 350 million chronic carriers worldwide [1]. The small HBV genome contains multiple translational reading frames to produce different HBV proteins [2]. These open reading frames (ORFs) include; S, C, P and X. The S ORF codes for the hepatitis B surface antigen (HBsAg). The C ORF codes for the core (HBcAg) and the e antigen (HBeAg) proteins. HBV core protein contains a cluster of highly basic amino acids and intrinsically has a property of self-assembly and RNA binding. The P ORF codes for the polymerase protein, which contains a reverse transcriptase activity that catalyzes the conversion of pregenomic RNA into viral DNA [2]. HBx is required for productive HBV replication [3]
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