School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland.
Biology Department, Maynooth University, Maynooth, Ireland.
FASEB J. 2019 Aug;33(8):8732-8744. doi: 10.1096/fj.201800629RR. Epub 2019 Jun 4.
Viruses use a spectrum of immune evasion strategies that enable infection and replication. The acute phase of hepatitis C virus (HCV) infection is characterized by nonspecific and often mild clinical symptoms, suggesting an immunosuppressive mechanism that, unless symptomatic liver disease presents, allows the virus to remain largely undetected. We previously reported that HCV induced the regulatory protein suppressor of cytokine signaling (SOCS)3, which inhibited TNF-α-mediated inflammatory responses. However, the mechanism by which HCV up-regulates SOCS3 remains unknown. Here we show that the HCV protein, p7, enhances both SOCS3 mRNA and protein expression. A p7 inhibitor reduced SOCS3 induction, indicating that p7's ion channel activity was required for optimal up-regulation of SOCS3. Short hairpin RNA and chemical inhibition revealed that both the Janus kinase-signal transducer and activator of transcription (JAK-STAT) and MAPK pathways were required for p7-mediated induction of SOCS3. HCV-p7 expression suppressed TNF-α-mediated IκB-α degradation and subsequent NF-κB promoter activity, revealing a new and functional, anti-inflammatory effect of p7. Together, these findings identify a molecular mechanism by which HCV-p7 induces SOCS3 through STAT3 and ERK activation and demonstrate that p7 suppresses proinflammatory responses to TNF-α, possibly explaining the lack of inflammatory symptoms observed during early HCV infection.-Convery, O., Gargan, S., Kickham, M., Schroder, M., O'Farrelly, C., Stevenson, N. J. The hepatitis C virus (HCV) protein, p7, suppresses inflammatory responses to tumor necrosis factor (TNF)-α signal transducer and activator of transcription (STAT)3 and extracellular signal-regulated kinase (ERK)-mediated induction of suppressor of cytokine signaling (SOCS)3.
病毒利用一系列免疫逃避策略来实现感染和复制。丙型肝炎病毒 (HCV) 感染的急性期表现为非特异性且常为轻度的临床症状，这表明存在免疫抑制机制，使病毒在无症状肝脏疾病出现之前在很大程度上未被检测到。我们之前报道过 HCV 诱导调节蛋白细胞因子信号转导抑制因子 (SOCS)3，SOCS3 抑制 TNF-α 介导的炎症反应。然而，HCV 上调 SOCS3 的机制尚不清楚。在这里，我们发现 HCV 蛋白 p7 增强了 SOCS3 mRNA 和蛋白的表达。p7 抑制剂降低了 SOCS3 的诱导，表明 p7 的离子通道活性是 SOCS3 最佳上调所必需的。短发夹 RNA 和化学抑制表明 JAK-STAT 和 MAPK 途径都需要 p7 介导的 SOCS3 诱导。HCV-p7 表达抑制了 TNF-α 介导的 IκB-α 降解和随后的 NF-κB 启动子活性，揭示了 p7 的一种新的、功能性的抗炎作用。总之，这些发现确定了 HCV-p7 通过 STAT3 和 ERK 激活诱导 SOCS3 的分子机制，并表明 p7 抑制了 TNF-α 的促炎反应，这可能解释了在 HCV 感染早期观察到的缺乏炎症症状的现象。-Convery，O.，Gargan，S.，Kickham，M.，Schroder，M.，O'Farrelly，C.，Stevenson，N. J. 丙型肝炎病毒 (HCV) 蛋白 p7 通过信号转导和转录激活因子 (STAT)3 和细胞外信号调节激酶 (ERK) 介导的抑制细胞因子信号转导 (SOCS)3 的诱导来抑制肿瘤坏死因子 (TNF)-α 的炎症反应。
