Hepatitis C virus inhibits interferon signaling through up-regulation of protein phosphatase 2A
Hepatitis C virus inhibits interferon signaling through up-regulation of protein phosphatase 2A
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DOI：
10.1053/j.gastro.2003.10.076
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发表时间：
2004-01-01
期刊：
影响因子：
29.4
通讯作者：
Heim, MH
中科院分区：
文献类型：
--
作者：
Duong, FHT;Filipowicz, M;Heim, MH
背景与目的：为了建立慢性感染，丙型肝炎病毒必须逃避宿主的防御。丙型肝炎病毒蛋白在培养细胞和转基因小鼠肝细胞中的表达通过Jak-STAT(信号转导和转录激活因子)途径抑制干扰素-α诱导的细胞内信号转导。目前尚不清楚慢性丙型肝炎患者的干扰素-a信号是否也受到抑制，其分子机制也不清楚。方法：对慢性丙型肝炎患者肝活检组织中干扰素α诱导的信号转导进行了研究。在培养细胞、转基因小鼠和肝活检组织中分析了丙型肝炎病毒干扰Jak-STAT信号转导的分子机制。结果：与对照组相比，慢性丙型肝炎患者肝组织中干扰素-α诱导的STAT1的DNA结合显著受损。STAT1的酪氨酸和丝氨酸磷酸化。，但精氨酸31上的STAT1甲基化减少。STAT1低甲基化与PIAS1相关，PIAS1是STAT DNA结合的抑制因子。在丙型肝炎转基因小鼠的肝提取液和慢性丙型肝炎患者的肝活检组织中，发现蛋白磷酸酶2A的表达水平增加。PP2Ac在Huh7细胞中的过度表达导致STAT1的低甲基化，增加了与PIAS1的结合，并减少了干扰素α诱导的STAT1的DNA结合。结论：我们得出结论：丙型肝炎病毒通过上调PP2Ac、STAT1的低甲基化和增加STAT1-PIAS1的结合来干扰干扰素-α信号转导，导致干扰素-α刺激基因的转录激活减少。
Background & Aims: To establish a chronic infection, hepatitis C virus (HCV) has to evade the host defense. Expression of HCV proteins in cultured cells and in hepatocytes of transgenic mice inhibits interferon-alpha-induced intracellular signaling through the Jak-STAT (signal transducer and activator of transcription) pathway. It is not known if interferon-a signaling is inhibited in patients with chronic hepatitis C as well, and the molecular mechanisms are not well defined. Methods: Interferon alpha-induced signaling was investigated in liver biopsies from patients with chronic hepatitis C. The molecular mechanisms of HCV interference with Jak-STAT signaling were analyzed in cultured cells, HCV transgenic mice, and liver biopsies. Results: Interferon-alpha-induced DNA binding of STAT1 was significantly impaired in liver biopsies from patients with chronic hepatitis C compared with controls. Tyrosine and serine phosphorylation of STAT1. were intact, but methylation of STAT1 on arginine 31 was reduced. Hypomethylated STAT1 associated with PIAS1, an inhibitor of STAT DNA binding. Increased expression levels of Protein Phosphatase 2A were found in liver extracts from HCV transgenic mice and in liver biopsies of patients with chronic hepatitis C. Overexpression of PP2Ac in Huh7 cells resulted in hypomethylation of STAT1, increased binding to PIAS1, and reduced interferon-alpha-induced DNA binding of STAT1. Conclusions: We conclude that HCV interferes with interferon-alpha signaling via up-regulation of PP2Ac, hypomethylation of STAT1, and increased STAT1-PIAS1 association, resulting in reduced transcriptional activation of interferon-alpha-stimulated genes.