Functional Study of Autophagic Response in Suppression of Type I Interferon Response

Autophagy is a stress-responsive and catabolic process by which cells degrade cytoplasmic components within lysosome to maintain cellular homeostasis. Autophagic response has long been known to be a bulk proteolytic pathway without selectivity. However, accumulated lines of evidence recently indicate that autophagic process can selectively eliminate unwanted components such as protein aggregates, dysfunctional organelles, and invading pathogens via lysosomal proteolysis. Analogous to other RNA viruses, hepatitis C virus (HCV) infection induces host cellular autophagy to benefit virus growth. Our previous study has demonstrated that HCV infection activates the complete autophagic process throughout to mature autolysosome to promote viral RNA replication via suppressing the HCV-derived pathogen-associated molecular pattern (PAMP)-induced type I interferon (IFN) antiviral response (Journal of Clinical Investigation, 2011). Similarly, activated autophagic response also represses the IFN innate immunity triggered by the PAMPs of other RNA viruses, e.g. dengue virus (DENV). These results conclude that HCV and its flaviviral relatives-induced autophagy pathway can negatively modulate type I IFN antiviral response, thus promoting viral life cycle. Nevertheless, the molecular mechanism responsible for how the autophagic process suppresses the viral PAMP-triggered RIG-I-like receptor (RLR) signaling and IFN immune response to protect viruses against antiviral immune defense still remain enigmatic. In addition, whether and how autophagy exerts its own selective proteolysis to inhibit type I IFN antiviral response is also poorly understood. Therefore, the overall goal of this three-year research proposal is to decipher the physiological significance of HCV-induced autophagy in suppression of RLR-mediated IFN antiviral response. Unveiling of the detailed molecular mechanism underlying this repressive process will provide a framework for the rational-design of feasible anti-HCV therapies or intervention applications. Toward this end, we set up the following specific aims, Aim I: To investigate whether autophagy alters RLR- and IFN-mediated signal transductions to repress type I IFN antiviral immunity. Aim II: To analyze whether autophagy targets RLR- and IFN-signaling molecules to degradation to downregulate type I IFN activation. Aim III: To examine whether HCV-induced autophagy suppresses type I IFN antiviral response via mitophagy. Aim IV: To identify the substrate proteins targeted to selective proteolysis by HCV-induced autophagy and investigate the physiological relevance with repression of type I IFN innate immunity. The results obtained in this proposal will provide the molecular basis of how autophagic process modulates the signal transductions, protein transport, or protein degradations of RLR and IFN signaling molecules to downregulate anti-HCV IFN immune response. Besides this, the accompaniment of these proposed studies will delineate the physiological relevance between the targeting of mitochondria to degradation with autophagic response as well as the repression of type I IFN-dependent antiviral immunity. Overall, these studies not only advance our knowledge of how autophagic proteolysis protects HCV against innate antiviral response, but also greatly shed insights on developing a new treatment strategy against HCV infection.

Project ID:PC10401-0203
External Project ID:NSC102-2320-B182-037-MY3