The protein kinase IKKε can inhibit HCV expression independently of IFN and its own expression is downregulated in HCV-infected livers

✍ Scribed by Myriam Vilasco; Esther Larrea; Damien Vitour; Stephanie Dabo; Adrien Breiman; Béatrice Regnault; Jose-Ignacio Riezu; Pierre Eid; Jesus Prieto; Eliane F. Meurs

• Publisher: John Wiley and Sons
• Year: 2006
• Tongue: English
• Weight: 704 KB
• Volume: 44
• Category: Article
• ISSN: 0270-9139
• DOI: 10.1002/hep.21432

✦ Synopsis

During a viral infection, binding of viral double-stranded RNAs (dsRNAs) to the cytosolic RNA helicase RIG-1 leads to recruitment of the mitochondria-associated Cardif protein, involved in activation of the IRF3-phosphorylating IKK⑀/TBK1 kinases, interferon (IFN) induction, and development of the innate immune response. The hepatitis C virus (HCV) NS3/4A protease cleaves Cardif and abrogates both IKK⑀/TBK1 activation and IFN induction. By using an HCV replicon model, we previously showed that ectopic overexpression of IKK⑀ can inhibit HCV expression. Here, analysis of the IKK⑀ transcriptome profile in these HCV replicon cells showed induction of several genes associated with the antiviral action of IFN. Interestingly, IKK⑀ still inhibits HCV expression in the presence of neutralizing antibodies to IFN receptors or in the presence of a dominant negative STAT1␣ mutant. This suggests that good IKK⑀ expression levels are important for rapid activation of the cellular antiviral response in HCV-infected cells, in addition to provoking IFN induction. To determine the physiological importance of IKK⑀ in HCV infection, we then analyzed its expression levels in liver biopsy specimens from HCVinfected patients. This analysis also included genes of the IFN induction pathway (RIG-I, MDA5, LGP2, Cardif, TBK1), and three IKK⑀-induced genes (IFN-␤, CCL3, and ISG15). The results show significant inhibition of expression of IKK⑀ and of the RNA helicases RIG-I/MDA5/LGP2 in the HCV-infected patients, whereas expression of TBK1 and Cardif was not significantly altered. In conclusion, given the antiviral potential of IKK⑀ and of the RNA helicases, these in vivo data strongly support an important role for these genes in the control of HCV infection. Supplementary material for this article can be found on the HEPATOLOGY website (http:// interscience.wiley.com/jpages/0270-9139/suppmat/index.html).