Correlation of Hepatitis C Virus-mediated Endoplasmic Reticulum Stress with Autophagic Flux Impairment and Hepatocarcinogenesis

Overview

Journal Med Mol Morphol

Publisher Springer

Specialties Cell Biology
Molecular Biology
Pathology

Date 2021 Jan 2

PMID 33386512

Citations 5

Authors

Yuichi Honma

Koichiro Miyagawa

Yuichi Hara

Tsuguru Hayashi

Masashi Kusanaga

Noriyoshi Ogino

Sota Minami

Shinji Oe

Masanori Ikeda

Keisuke Hino

Masaru Harada

Affiliations

Soon will be listed here.

Abstract

Hepatitis C virus (HCV) infection has been known to use autophagy for its replication. However, the mechanisms by which HCV modulates autophagy remain controversial. We used HCV-Japanese fulminant hepatitis-1-infected Huh7 cells. HCV infection induced the accumulation of autophagosomes. Morphological analyses of monomeric red fluorescent protein (mRFP)-green fluorescent protein (GFP) tandem fluorescent-tagged LC3 transfection showed HCV infection impaired autophagic flux. Autophagosome-lysosome fusion assessed by transfection of mRFP- or GFP-LC3 and immunostaining of lysosomal-associated membrane protein 1 was inhibited by HCV infection. Decrease of HCV-induced endoplasmic reticulum (ER) stress by 4-phenylbutyric acid, a chemical chaperone, improved the HCV-mediated autophagic flux impairment. HCV infection-induced oxidative stress and subsequently DNA damage, but not apoptosis. Furthermore, HCV induced cytoprotective effects against the cellular stress by facilitating the formation of cytoplasmic inclusion bodies as shown by p62 expression and by modulating keratin protein expression and activated nuclear factor erythroid 2-related factor 2. HCV eradication by direct-acting antivirals improved autophagic flux, but DNA damage persisted. In conclusion, HCV-induced ER stress correlates with autophagic flux impairment. Decrease of ER stress is considered to be a promising therapeutic strategy for HCV-related chronic liver diseases. However, we should be aware that the risk of hepatocarcinogenesis remains even after HCV eradication.

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