Molecular Mechanism of Selective Autophagy in Regulation of Rlr Antiviral Signaling

Autophagy is a stress-responsive process by which cells break down cytoplasmic components to maintain cellular homeostasis. Emerging lines of evidence indicate that autophagic process can selectively target the damaged organelles or proteins to lysosomal degradation. Several RNA viruses, including hepatitis C virus (HCV), activate autophagy to benefit virus growth in the infected host cells. We previously demonstrated that HCV infection induces the complete autophagic process throughout to mature autolysosome to promote viral replication via repressing the interferon (IFN)-mediated immune response (Journal of Clinical Investigation, 2011). However, how the autophagic process suppresses RIG-I-like receptor (RLR) signaling to help HCV to evade antiviral immune defense still remains largely unknown. Moreover, whether the HCV-triggered autophagy exerts its own selective proteolysis to repress RLR antiviral defense is also poorly understood. Thus, the objective of this three-year research proposal is to investigate the physiological role of HCV-induced autophagy in negative modulation of RLR antiviral signaling. Unveiling of the detailed molecular mechanism underlying this suppressive process will be used as a basis for rational-design of a novel anti-HCV therapy. To this end, we set up three specific aims as the follows, Aim I. To explore whether autophagy represses RLR-mediated antiviral immunity through regulating the expressions and activations of RLR-signaling molecules. Aim II. To investigate how autophagy downregulates RLR-mediated antiviral response via selectively targeting of RLR-signaling molecules to degradation. Aim III. To examine whether autophagy suppresses RLR antiviral immune response by altering the dynamics of mitochondria through mitophagy. Accomplishment of these studies proposed in this research project will delineate the molecular mechanism underlying how autophagic process suppresses anti-HCV immune signaling via altering signaling transduction, protein trafficking, or protein degradation of RLR-signaling molecules. Most importantly, the completion of this proposal also provides significance for the physiological relevance between mitochondrial dynamics and RLR antiviral response. Overall, these studies not only advance our knowledge of how autophagic proteolysis protects HCV against innate immune response, but also greatly shed insights on developing a new treatment strategy against HCV infection.

Project ID:PC10108-0534
External Project ID:NSC101-2320-B182-043