Statins enhance extracellular release of hepatitis C virus particles through ERK5 activation

IF 1.9 4区 医学 Q4 IMMUNOLOGY
Chie Aoki-Utsubo, Masanori Kameoka, Lin Deng, Muhammad Hanafi, Beti Ernawati Dewi, Pratiwi Sudarmono, Takaji Wakita, Hak Hotta
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引用次数: 0

Abstract

Statins, such as lovastatin, have been known to inhibit 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase. Statins were reported to moderately suppress hepatitis C virus (HCV) replication in cultured cells harboring HCV RNA replicons. We report here using an HCV cell culture (HCVcc) system that high concentrations of lovastatin (5–20 μg/mL) markedly enhanced the release of HCV infectious particles (virion) in the culture supernatants by up to 40 times, without enhancing HCV RNA replication, HCV protein synthesis, or HCV virion assembly in the cells. We also found that lovastatin increased the phosphorylation (activation) level of extracellular-signal-regulated kinase 5 (ERK5) in both the infected and uninfected cells in a dose-dependent manner. The lovastatin-mediated increase of HCV virion release was partially reversed by selective ERK5 inhibitors, BIX02189 and XMD8-92, or by ERK5 knockdown using small interfering RNA (siRNA). Moreover, we demonstrated that other cholesterol-lowering statins, but not dehydrolovastatin that is incapable of inhibiting HMG-CoA reductase and activating ERK5, enhanced HCV virion release to the same extent as observed with lovastatin. These results collectively suggest that statins markedly enhance HCV virion release from infected cells through HMG-CoA reductase inhibition and ERK5 activation.

他汀类药物通过激活 ERK5 增强丙型肝炎病毒颗粒的细胞外释放。
众所周知,他汀类药物(如洛伐他汀)可抑制 3-羟基-3-甲基戊二酰辅酶 A(HMG-CoA)还原酶。据报道,他汀类药物可适度抑制丙型肝炎病毒(HCV)在含有 HCV RNA 复制子的培养细胞中的复制。我们在此使用 HCV 细胞培养(HCVcc)系统报告,高浓度的洛伐他汀(5-20 μg/mL)可显著增强培养上清中 HCV 感染性颗粒(病毒)的释放,最多可增强 40 倍,而不会增强细胞中 HCV RNA 复制、HCV 蛋白合成或 HCV 病毒组装。我们还发现,洛伐他汀能以剂量依赖的方式提高感染细胞和未感染细胞中细胞外信号调节激酶5(ERK5)的磷酸化(激活)水平。选择性ERK5抑制剂BIX02189和XMD8-92或使用小干扰RNA(siRNA)敲除ERK5可部分逆转洛伐他汀介导的HCV病毒释放增加。此外,我们还证明了其他降低胆固醇的他汀类药物(但不包括不能抑制 HMG-CoA 还原酶和激活 ERK5 的脱氢洛伐他汀)也能促进 HCV 病毒的释放,其程度与洛伐他汀所观察到的相同。这些结果共同表明,他汀类药物通过抑制HMG-CoA还原酶和激活ERK5,显著增强了感染细胞中HCV病毒的释放。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Microbiology and Immunology
Microbiology and Immunology 医学-免疫学
CiteScore
5.20
自引率
3.80%
发文量
78
审稿时长
1 months
期刊介绍: Microbiology and Immunology is published in association with Japanese Society for Bacteriology, Japanese Society for Virology, and Japanese Society for Host Defense Research. It is peer-reviewed publication that provides insight into the study of microbes and the host immune, biological and physiological responses. Fields covered by Microbiology and Immunology include:Bacteriology|Virology|Immunology|pathogenic infections in human, animals and plants|pathogenicity and virulence factors such as microbial toxins and cell-surface components|factors involved in host defense, inflammation, development of vaccines|antimicrobial agents and drug resistance of microbes|genomics and proteomics.
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