Correlation of hepatitis C virus-mediated endoplasmic reticulum stress with autophagic flux impairment and hepatocarcinogenesis
Correlation of hepatitis C virus-mediated endoplasmic reticulum stress with autophagic flux impairment and hepatocarcinogenesis
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DOI：
10.1007/s00795-020-00271-5
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发表时间：
2021-01-01
影响因子：
1.8
通讯作者：
Harada, Masaru
中科院分区：
文献类型：
--
作者：
Honma, Yuichi;Miyagawa, Koichiro;Harada, Masaru
已知丙型肝炎病毒（HCV）感染利用自噬进行复制。然而，HCV调节自噬的机制仍然存在争议。我们使用HCV-日本暴发性肝炎-1-感染的Huh 7细胞。HCV感染诱导自噬体的积累。形态学分析表明，单体红色荧光蛋白（mRFP）-绿色荧光蛋白（GFP）串联荧光标记的LC 3转染HCV感染损害自噬通量。通过转染mRFP或GFP-LC 3和溶酶体相关膜蛋白1的免疫染色评估的自噬体-溶酶体融合被HCV感染抑制。4-苯基丁酸（一种化学伴侣）减少HCV诱导的内质网（ER）应激，改善了HCV介导的自噬通量损伤。HCV感染诱导的氧化应激和随后的DNA损伤，但不是凋亡。此外，HCV通过促进细胞质包涵体的形成（如p62表达所示）以及通过调节角蛋白表达和活化核因子红细胞2相关因子2诱导细胞保护作用对抗细胞应激。通过直接作用的抗病毒药物根除HCV改善了自噬通量，但DNA损伤持续存在。总之，HCV诱导的ER应激与自噬通量受损相关。降低内质网应激被认为是治疗HCV相关慢性肝病的一个有前途的策略。然而，我们应该意识到，即使在HCV根除后，肝癌发生的风险仍然存在。
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.