Editors' ChoiceHost-Pathogen Interactions

Channel Shutdown

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Science Signaling  22 Sep 2009:
Vol. 2, Issue 89, pp. ec310
DOI: 10.1126/scisignal.289ec310

Hepatitis C virus (HCV) maintains a persistent infection that is essential for its survival; however, the mechanisms involved are not well characterized. Mankouri et al. postulated that HCV might target channel proteins—in particular, K+ channels that mediate efflux of K+ before apoptosis. Patch-clamp experiments showed that K+ currents present in human hepatoma Huh-7 cells were absent from Huh-7 cells stably expressing HCV genes that encode nonstructural proteins. K+ channel activity was also inhibited in HCV-infected cells compared with that in uninfected cells. Transfection studies showed that the nonstructural protein NS5A was sufficient to inhibit K+ efflux in Huh-7 cells, and experiments with blocking antibodies identified Kv2.1 as its likely target. Kv2.1 is activated by oxidative stress after its phosphorylation by the mitogen-activated protein kinase p38. The authors showed that activation of Kv2.1 in Huh-7 cells by the oxidizing agent DTDP was blocked if the cells contained nonstructural HCV proteins. Western blotting analysis showed that DTDP triggered the phosphorylation (and activation) of p38, which was blocked by NS5A but not by a variant NS5A with a mutated Src homology (SH3) domain (NS5A PA2). Kv2.1 was phosphorylated in DTDP-treated control cells but not in treated cells that contained NS5A. Finally, cells transfected with HCV genes including the gene encoding NS5A were less likely to undergo apoptosis than those cells that received the gene encoding the NS5A PA2 mutant. Together, these data suggest that HCV specifically targets the p38-dependent activation of Kv2.1 to reduce K+ efflux, thus inhibiting apoptosis and enabling persistent infection.

J. Mankouri, M. L. Dallas, M. E. Hughes, S. D. C. Griffin, A. Macdonald, C. Peers, M. Harris, Suppression of a pro-apoptotic K+ channel as a mechanism for hepatitis C virus persistence. Proc. Natl. Acad. Sci. U.S.A. 106, 15903–15908 (2009). [Abstract] [Full Text]

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