Editors' ChoiceVirology

Mimicry in Akt-ion

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Science Signaling  21 Dec 2010:
Vol. 3, Issue 153, pp. ec386
DOI: 10.1126/scisignal.3153ec386

Viruses have evolved various strategies for evading host responses, including mechanisms for overcoming host cell translational blocks that halt viral replication. Many of these depend on targeting signaling through the mammalian target of rapamycin complex 1 (mTORC1), a key regulator of translation initiation. Phosphorylation of tuberous sclerosis complex 2 (TSC2) by Akt leads to activation of mTORC1, which, in turn, leads to phosphorylation of the regulator of translation initiation 4E-BP1 and subsequent stimulation of translation. Chuluunbaatar et al. report that the serine-threonine kinase Us3 from herpes simplex virus–1 (HSV-1) mimics Akt activity despite having no sequence homology with it. Us3 was required for efficient viral replication and for infection-induced accumulation of phosphorylated forms of both 4E-BP1 and TSC2 in infected human fibroblasts. Cell culture and in vitro assays demonstrated that TSC2 was a direct target of Us3 and that HSV-1–induced phosphorylation of 4E-BP1 depended on Us3 phosphorylating TSC2. Knocking down TSC2 by RNA interference enhanced replication of a mutant virus lacking Us3 but did not fully restore replication of the mutant virus to wild-type (WT) levels, suggesting that Us3 likely has additional cellular targets. Indeed, Us3 phosphorylated the Akt targets FOXO1 and GSK3 in HSV-infected cells and in cells expressing a tagged version of Us3 from a transgene. Molecular phylogenetics indicated that Us3 was no more closely related to the Akt subfamily of serine-threonine kinases than it was to other subfamilies, implying that it is unlikely to be subject to modulation by cellular regulators of Akt. Given that drugs that target mTORC are immunosuppressive, developing inhibitors of Us3 might offer a means for managing outbreaks of HSV-1 without compromising host cell functions.

U. Chuluunbaatar, R. Roller, M. E. Feldman, S. Brown, K. M. Shokat, I. Mohr, Constitutive mTORC1 activation by a herpesvirus Akt surrogate stimulates mRNA translation and viral replication. Genes Dev. 24, 2627–2639 (2010). [Abstract] [Full Text]

K. L. Norman, P. Sarnow, Herpes Simplex Virus is Akt-ing in translational control. Genes Dev. 24, 2583–2586 (2010). [Abstract] [Full Text]

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