The alpha isoform of protein kinase CKI is responsible for hepatitis C virus NS5A hyperphosphorylation.
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Quintavalle M, Sambucini S, Di Pietro C, De Francesco R, Neddermann P
The alpha isoform of protein kinase CKI is responsible for hepatitis C virus NS5A hyperphosphorylation.
J Virol. 2006 Nov;80(22):11305-12. Epub 2006 Aug 30.
- PubMed ID
- 16943283 [ View in PubMed]
- Abstract
Hepatitis C virus (HCV) has been the subject of intensive studies for nearly two decades. Nevertheless, some aspects of the virus life cycle are still a mystery. The HCV nonstructural protein 5A (NS5A) has been shown to be a modulator of cellular processes possibly required for the establishment of viral persistence. NS5A is heavily phosphorylated, and a switch between a basally phosphorylated form of NS5A (p56) and a hyperphosphorylated form of NS5A (p58) seems to play a pivotal role in regulating HCV replication. Using kinase inhibitors that specifically inhibit the formation of NS5A-p58 in cells, we identified the CKI kinase family as a target. NS5A-p58 increased upon overexpression of CKI-alpha, CKI-delta, and CKI-epsilon, whereas the RNA interference of only CKI-alpha reduced NS5A hyperphosphorylation. Rescue of inhibition of NS5A-p58 was achieved by CKI-alpha overexpression, and we demonstrated that the CKI-alpha isoform is targeted by NS5A hyperphosphorylation inhibitors in living cells. Finally, we showed that down-regulation of CKI-alpha attenuates HCV RNA replication.