Chaperone-Mediated Autophagy Promotes Beclin1 Degradation in Persistently Infected Hepatitis C Virus (HCV) Cell Culture.

Liver cirrhosis is an independent risk factor for hepatocellular carcinoma (HCC). The mechanisms contributing to HCC development in cirrhotic microenvironment are unknown. We demonstrated that HCC grown in the highly stressed cirrhotic microenvironment undergoes autophagy switching from a protective state characterized by high macroautophagy with low chaperone-mediated autophagy (CMA) to an HCC-promoting state low macroautophagy with high CMA. This study was performed to understand how the stress response executes oncogenic cell programming through autophagy switching using hepatitis C virus cell culture. Protein kinase R-like ER kinase expression increased to high-levels in hepatitis C Virus culture. Protein kinase R-like ER kinase-dependent activation of nuclear factor erytroid 2-related factor (Nrf2) led to increased transcription of the cytoprotective genes: heat shock cognate 70 kDa protein (Hsc70) and lysosome-associated membrane protein type 2A (LAMP2A) and precipitated the induction of CMA. CMA selectively targeted beclin1 degradation, leading to accumulation of the autophagy flux protein p62 due to impaired autophagosome-endosome fusion. This impaired autophagosome-endosome fusion due to beclin1 degradation inhibited endocytosis and degradation of epidermal growth factor receptor. Silencing Nrf2 and LAMP2A reduced cell viability, suggesting that the stress response activates CMA as a compensatory mechanism of cell survival. In conclusion, we report here a novel mechanism through which stress response triggers oncogenic Nrf2 signaling that promotes autophagy switching to favor cell survival.