Destabilization of PDK1 by Hsp90 inactivation suppresses hepatitis C virus replication through inhibition of PRK2-mediated viral RNA polymerase phosphorylation

Mi Gyeong Kim, Jae Su Moon, Eun Jung Kim, Seung Hoon Lee, Jong Won Oh

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

Heat shock protein 90 (Hsp90), which chaperones multiple client proteins, has been shown to be implicated in HCV replication. Pharmacological inhibitors of Hsp90 display an anti-HCV activity. However, little is known about the mechanisms of regulation of HCV replication by Hsp90. Here, we show that Hsp90 inhibition by 17-(dimethylaminoethylamino)-17-demethoxygeldanamycin (17-DMAG) destabilizes phosphoinositide-dependent kinase-1 (PDK1), an upstream kinase of the protein kinase C-related kinase 2 (PRK2) responsible for phosphorylation of HCV RNA polymerase, through the proteosome pathway. Destabilization of PDK1 led to inhibition of phosphorylation of the viral RNA polymerase through a decrease in the abundance of active form PRK2 level. Consequently, Hsp90 inhibition resulted in suppression of HCV replication both in human hepatoma Huh7 cells harboring an HCV subgenomic replicon and in HCV-infected cells. 17-DMAG treatment did not interfere with HCV internal ribosome entry site-mediated translation and the cell cycle in Huh7 cells. Co-treatment of 17-DMAG with interferon-α or HA1077, an inhibitor of PRK2, enhanced the anti-HCV activity of 17-DMAG. Taken together, these findings suggest that Hsp90 plays a critical role in the regulation of HCV RNA polymerase phosphorylation via the PDK1-PRK2 signaling pathway.

Original languageEnglish
Pages (from-to)112-118
Number of pages7
JournalBiochemical and Biophysical Research Communications
Volume421
Issue number1
DOIs
Publication statusPublished - 2012 Apr 27

Bibliographical note

Funding Information:
This work was supported by a grant from the National Research Foundation of Korea ( NRF-2011-0027650 ), and in part by the Technology Innovation Program ( MKE 10035159 ) funded by the Ministry of Knowledge Economy (MKE, Korea) and by grants from National Research Foundation of Korea ( NRF 2011-0001236 and 2010-0029116 ).

All Science Journal Classification (ASJC) codes

  • Biophysics
  • Biochemistry
  • Molecular Biology
  • Cell Biology

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