Convery, Orla and Gargan, Siobhan and Kickham, Michelle and Schröder, Martina and O'Farrelly, Cliona and Stevenson, Nigel J. (2019) The hepatitis C virus (HCV) protein, p7, suppresses inflammatory responses to tumor necrosis factor (TNF)-alpha via signal transducer and activator of transcription (STAT)3 and extracellular signal-regulated kinase (ERK)-mediated induction of suppressor of cytokine signaling (SOCS)3. FASEB Journal, 33 (8). pp. 8732-8744. ISSN 1530-6860

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Abstract

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 via signal transducer and activator of transcription (STAT)3 and extracellular signal-regulated kinase (ERK)-mediated induction of suppressor of cytokine signaling (SOCS)3.

Item Type:	Article
Keywords:	JAK-STAT signalling pathway; immune regulation; inflammation; intracellular signaling pathways; viral immune evasion;
Academic Unit:	Faculty of Science and Engineering > Biology
Item ID:	13857
Identification Number:	https://doi.org/10.1096/fj.201800629RR
Depositing User:	Martina Schroeder
Date Deposited:	22 Jan 2021 11:20
Journal or Publication Title:	FASEB Journal
Publisher:	Federation of American Society of Experimental Biology
Refereed:	Yes
URI:	Publisher
Use Licence:	This item is available under a Creative Commons Attribution Non Commercial Share Alike Licence (CC BY-NC-SA). Details of this licence are available here

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