Chaperone-Mediated Autophagy in the Liver: Good or Bad?

Abstract

Hepatitis C virus (HCV) infection triggers autophagy processes, which help clear out the dysfunctional viral and cellular components that would otherwise inhibit the virus replication. Increased cellular autophagy may kill the infected cell and terminate the infection without proper regulation. The mechanism of autophagy regulation during liver disease progression in HCV infection is unclear. The autophagy research has gained a lot of attention recently since autophagy impairment is associated with the development of hepatocellular carcinoma (HCC). Macroautophagy, microautophagy, and chaperone-mediated autophagy (CMA) are three autophagy processes involved in the lysosomal degradation and extracellular release of cytosolic cargoes under excessive stress. Autophagy processes compensate for each other during extreme endoplasmic reticulum (ER) stress to promote host and microbe survival as well as HCC development in the highly stressed microenvironment of the cirrhotic liver. This review describes the molecular details of how excessive cellular stress generated during HCV infection activates CMA to improve cell survival. The pathological implications of stress-related CMA activation resulting in the loss of hepatic innate immunity and tumor suppressors, which are most often observed among cirrhotic patients with HCC, are discussed. The oncogenic cell programming through autophagy regulation initiated by a cytoplasmic virus may facilitate our understanding of HCC mechanisms related to non-viral etiologies and metabolic conditions such as uncontrolled type II diabetes. We propose that a better understanding of how excessive cellular stress leads to cancer through autophagy modulation may allow therapeutic development and early detection of HCC.

LAMP3 induces apoptosis and autoantigen release in Sjögren’s syndrome patients

“…Lysosomal proteins are key components involved in antigen presentation and cell survival 10 , 11 . Unlike canonical lysosome-associated membrane proteins such as LAMP1 and LAMP2, LAMP3 is tightly regulated and its expression is induced during infection 12 .…”

HSP90α Mediates Sorafenib Resistance in Human Hepatocellular Carcinoma by Necroptosis Inhibition under Hypoxia

“…Chaperone-mediated autophagy (CMA) is a lysosomal pathway of proteolysis that is responsible for the degradation of 30% of cytosolic proteins [ 31 , 32 ]. HSP70 and HSP90 is the most essential component for protein transport across the lysosomal membrane in process of CMA [ 33 , 34 ]. They cannot only locate the substrate protein, but also recognize substrate protein.…”

Nrf2 in Neoplastic and Non-Neoplastic Liver Diseases

“…In the autophagy context, it is important to underline that, together with the canonical (ROS-dependent, KEAP1-dependent) and non-canonical (p62-dependent) mechanisms of NRF2 activation, endoplasmic reticulum (ER) stress represents an additional connection between autophagy and Nrf2 [ 143 , 144 ]. Indeed, eukaryotic translation initiation factor 2 alpha kinase 3 (PERK), a type I ER transmembrane protein which participates in the regulation of the Glucose regulatory protein 78 (GRP78) [ 145 ], in response to proteins accumulated in the ER lumen, is separated from Keap1 and phosphorylates Nrf2 [ 146 ], allowing its nuclear translocation, and activation of cell survival signals.…”