Chaperone-Mediated Autophagy Promotes Beclin1 Degradation in Persistently Infected Hepatitis C Virus Cell Culture

• Published in: The American journal of pathology Vol. 188; no. 10; pp. 2339 - 2355
• Main Authors: Aydin, Yucel, Stephens, Christopher M., Chava, Srinivas, Heidari, Zahra, Panigrahi, Rajesh, Williams, Donkita D., Wiltz, Kylar, Bell, Antoinette, Wilson, Wallace, Reiss, Krzysztof, Dash, Srikanta
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.10.2018; American Society for Investigative Pathology
• Subjects: Autophagy - physiology; Beclin-1 - metabolism; Cell Survival - physiology; Cells, Cultured; Gene Silencing - physiology; Hepacivirus - physiology; Hepatitis C, Chronic - physiopathology; Hepatocytes - physiology; Humans; Lysosomal Membrane Proteins - physiology; Molecular Chaperones - physiology; Neoplasm Proteins - physiology; NF-E2-Related Factor 2 - physiology; Signal Transduction - physiology; Stress, Physiological - physiology; Virus Replication - physiology
• ISSN: 0002-9440; 1525-2191
• DOI: 10.1016/j.ajpath.2018.06.022

Liver cirrhosis is an independent risk factor for hepatocellular carcinoma (HCC). The mechanisms that contribute to HCC development in the cirrhotic microenvironment are unknown. We found 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 characterized by low macroautophagy with high CMA. This study examined how the stress response executes oncogenic cell programming through autophagy switching using hepatitis C virus cell culture. Protein kinase R–like endoplasmic reticulum kinase expression increased to high levels in hepatitis C virus culture. Protein kinase R–like endoplasmic reticulum kinase–dependent activation of nuclear factor erythroid 2–related factor (Nrf2) led to increased transcription of the cytoprotective genes: heat shock cognate 70 kDa protein and lysosome-associated membrane protein 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. We report a novel mechanism through which stress response triggers oncogenic Nrf2 signaling that promotes autophagy switching to favor cell survival.