Acetaldehyde Disrupts Interferon Alpha Signaling in Hepatitis C Virus-Infected Liver Cells by Up-Regulating USP18.
Acetaldehyde Disrupts Interferon Alpha Signaling in Hepatitis C Virus-Infected Liver Cells by Up-Regulating USP18.
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DOI：
10.1111/acer.13226
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发表时间：
2016-11
期刊：
影响因子：
--
通讯作者：
Osna NA
中科院分区：
文献类型：
--
作者：
Ganesan M;Poluektova LY;Tuma DJ;Kharbanda KK;Osna NA
饮酒加剧了丙型肝炎病毒感染的发病机制，并使疾病结局恶化。确切的原因尚不清楚，但可能部分归因于酒精进一步抑制先天免疫的能力。已知先天免疫已被肝细胞中的HCV降低。在这项研究中，我们旨在探讨酒精代谢如何失调HCV+肝癌细胞中IFNα信号通路（STAT1磷酸化）的机制。为此，CYP2E1+ Huh7.5细胞感染HCV并暴露于乙醛生成系统（AGS）。连续产生的乙醛抑制IFNα诱导的STAT1磷酸化，但增加蛋白酶USP18的水平（均通过Western blot测量），干扰IFNα信号传导。在原代人肝细胞培养物和乙醇喂养的HCV转基因小鼠的肝脏中证实了乙醛诱导USP18的作用。通过特异性siRNA沉默USP18可减弱乙醛对pSTAT1的抑制。乙醛下调pSTAT1的机制与IFNα r2和USP18之间的相互作用增强有关，这种相互作用最终导致细胞表面IFN受体与STAT1之间的串扰失调。此外，乙醛降低STAT1的isg酰化（小泛素样修饰物ISG15的蛋白偶联，Western blot），从而保持STAT1的激活。抑制isg酰化导致STAT1 K48多泛素化增加，从而允许pSTAT1被蛋白酶体降解。我们得出结论，乙醛通过上调USP18破坏ifn α-诱导的STAT1磷酸化，从而阻断hcv感染肝细胞的先天免疫保护，从而促进hcv -酒精发病。这在一定程度上可以解释酒精滥用患者丙型肝炎病毒感染恶化/进展的机制。
Alcohol consumption exacerbates the pathogenesis of HCV-infection and worsens disease outcomes. The exact reasons are not clear yet, but they might be partially attributed to the ability of alcohol to further suppress innate immunity. Innate immunity is known to be already decreased by HCV in liver cells. In this study, we aimed to explore the mechanisms of how alcohol metabolism dysregulates IFNα signaling (STAT1 phosphorylation) in HCV+ hepatoma cells. To this end, CYP2E1+ Huh7.5 cells were infected with HCV and exposed to the acetaldehyde generating system (AGS). Continuously produced acetaldehyde suppressed IFNα-induced STAT1 phosphorylation, but increased the level of a protease, USP18 (both measured by Western blot), which interferes with IFNα signaling. Induction of USP18 by acetaldehyde was confirmed in primary human hepatocyte cultures and in livers of ethanol-fed HCV transgenic mice. Silencing of USP18 by specific siRNA attenuated the pSTAT1 suppression by acetaldehyde. The mechanism by which acetaldehyde downregulates pSTAT1 is related to an enhanced interaction between IFNαR2 and USP18 that finally dysregulates the cross-talk between the IFN receptor on the cell surface and STAT1. Furthermore, acetaldehyde decreases ISGylation of STAT1 (protein conjugation of a small ubiquitin-like modifier, ISG15, Western blot), which preserves STAT1 activation. Suppressed ISGylation leads to an increase in STAT1 K48 polyubiquitination which allows pSTAT1 degrading by proteasome. We conclude that acetaldehyde disrupts IFNα-induced STAT1 phosphorylation by the upregulation USP18 to block the innate immunity protection in HCV-infected liver cells, thereby contributing to HCV-alcohol pathogenesis. This, in part, may explain the mechanism of HCV-infection exacerbation/progression in alcohol-abusing patients.
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