The HCV protein, p7, suppresses inflammatory responses to TNF-a via STAT3 and ERK-mediated induction of SOCS3
Citation:
Convery O, Gargan S, Kickham M, Schroder M, O'Farrelly C and Stevenson NJ, The HCV protein, p7, suppresses inflammatory responses to TNF-a via STAT3 and ERK-mediated induction of SOCS3, The FASEB Journal, 33, 8, 2019, 8732 - 8744Download Item:
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-a–mediated inflammatory responses. However, the mechanism by which
HCVup-regulates SOCS3 remains unknown. Hereweshow thatthe HCV protein, p7, enhances bothSOCS3 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-a–mediated IkB-a degradation and sub-
sequent NF-kB 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-a, possibly explaining the lack of in-
flammatory 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)-a 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 J.
33, 8732–8744 (2019)
URI:
https://faseb.onlinelibrary.wiley.com/doi/10.1096/fj.201800629RRhttp://hdl.handle.net/2262/95581
Author's Homepage:
http://people.tcd.ie/stevennjDescription:
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Author: Stevenson, Nigel
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Journal ArticleURI:
https://faseb.onlinelibrary.wiley.com/doi/10.1096/fj.201800629RRhttp://hdl.handle.net/2262/95581
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The FASEB Journal;33;
8;
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Full text availableKeywords:
immunosuppressive, hepatitis C virus (HCV), TNF-a–mediated inflammatory responses, Inflammation, Viral immune evasion, Immune regulationDOI:
https://doi.org/10.1096/fj.201800629RRMetadata
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