Investigation on the Functional Role of Selective Autophagy on the Viral Entry (Co)Receptors-Host Cell Permissiveness Interactions

Autophagy, an evolutionarily conserved process by which cell promotes the breakdown of cytoplasmic components to regenerate energy and nutrients, thus promoting the maintenance of cellular homeostasis. In addition to be a bulk and non-selective degradation pathway, mounting lines of evidence recently indicate that autophagy exerts selective proteolysis that eliminates the damaged organelles, aggregated proteins, and invading pathogens through cargo receptor-dependent recognition process. Several RNA viruses, including hepatitis C virus (HCV) have been demonstrated to activate autophagy to benefit viral growth in infected cells. Our previous study showed that HCV infection induces the entire autophagic process throughout to mature autolysosome to promote viral replication by suppressing innate antiviral response (Journal of Clinical Investigation, 2011). However, whether the HCV-activated autophagy selectively targets the unknown cargoes to degradation and whether the viral-activated autophagy regulates HCV propagation in infected cells still remain obscure. On the other hand, our recent study demonstrated that highly active replication of HCV promotes the downregulations of viral entry (co)receptors (PLoS ONE, 2013). Moreover, our preliminary results indicated that HCV infection also leads to degradations of viral entry (co)receptors, which are accompanied by induction of selective autophagy. These results collectively suggest that selective autophagy may participate in downregulating the expressions of HCV entry (co)receptors through proteolysis, thus negatively modulating cell permissiveness to HCV reinfection. So far, the molecular mechanism underlying how selective autophagy promotes the degradations of viral entry (co)receptors is not understood. Thus, the objective of this three-year research proposal is to study the physiological significance of HCV-activated selective autophagy in the proteolysis of viral entry (co)receptors. To this end, we set up four specific aims as the follows, Aim I: To study how autophagy participates in HCV-induced downregulations of HCV entry (co)receptors. Aim II: To examine how selective autophagy promotes the proteolysis of HCV entry (co)receptors. Aim III: To delineate the molecular mechanism responsible for how selective autophagy degrades HCV entry (co)receptors. Aim IV: To decipher the physiological significance of selective autophagy-mediated proteolysis of HCV entry (co)receptors in virus-host cells interactions. Accomplishment of these studies proposed in this research plan will promote our knowledge of how HCV entry (co)receptors are polyubiquitinated by specific ubiquitin E3 ligases, recognized by cargo receptors of selective autophagy, and targeted to selective proteolysis via autophagic process. Most importantly, deciphering of this selective proteolysis process will shed insights to understand how host cellular autophagy act as a repressor to counteract productive HCV replication in infected cells, thereby balancing virus-host cells interactions. In perspective, this mode of host cell-HCV interaction not only has important implications to uncover the pathogenesis of HCV-associated liver diseases and to develop a new personal therapeutic strategy, but also shed light on understanding of the establishment of persistent infection by HCV and its flaviviral relatives. Successful completion of this research proposal will promote us to understand the pathogenesis of HCV-related diseases and also provide the molecular basis for the discovery of new therapy against HCV infection, a major burden to public health worldwide. Therefore, this proposal owns its potential profound influence on aspects of society, economics, and academic development.

Project ID:PC10601-0875
External Project ID:MOST105-2628-B182-001-MY3