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Journal of Virology, November 2006, p. 11305-11312, Vol. 80, No. 22
0022-538X/06/$08.00+0     doi:10.1128/JVI.01465-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

The {alpha} Isoform of Protein Kinase CKI Is Responsible for Hepatitis C Virus NS5A Hyperphosphorylation{triangledown}

Manuela Quintavalle, Sonia Sambucini, Chiara Di Pietro, Raffaele De Francesco, and Petra Neddermann*

Istituto di Ricerche di Biologia Molecolare "P. Angeletti," 00040 Pomezia (Roma), Italy

Received 11 July 2006/ Accepted 24 August 2006

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-{varepsilon}, 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.

* Corresponding author. Mailing address: Istituto di Ricerche di Biologia Molecolare "P. Angeletti," 00040 Pomezia (Roma), Italy. Phone: 39-06-91093221. Fax: 39-06-91093654. E-mail: Petra_Neddermann{at}merck.com.

{triangledown} Published ahead of print on 30 August 2006.

Journal of Virology, November 2006, p. 11305-11312, Vol. 80, No. 22
0022-538X/06/$08.00+0     doi:10.1128/JVI.01465-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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