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Genes & Dev. 24 (23): 2627-2639

Copyright © 2010 by Cold Spring Harbor Laboratory Press.

Constitutive mTORC1 activation by a herpesvirus Akt surrogate stimulates mRNA translation and viral replication

Uyanga Chuluunbaatar1,2, Richard Roller3, Morris E. Feldman4,5, Stuart Brown6, Kevan M. Shokat4,5,, and Ian Mohr1,2,7

1 Department of Microbiology, New York University School of Medicine, New York, New York 10016, USA;
2 New York University Cancer Institute, New York University School of Medicine, New York, New York 10016, USA;
3 Department of Microbiology, University of Iowa, Iowa City, Iowa 52242, USA;
4 Howard Hughes Medical Institute, University of California at San Francisco, San Francisco, California 9143, USA;
5 Department of Cellular and Molecular Pharmacology, University of California at San Francisco, San Francisco, California 9143, USA;
6 Center for Health Informatics and Bioinformatics, New York University School of Medicine, New York, New York, 10016, USA

Abstract: All viruses require cellular ribosomes to translate their mRNAs. Viruses producing methyl-7 (m7) GTP-capped mRNAs, like Herpes Simplex Virus-1 (HSV-1), stimulate cap-dependent translation by activating mTORC1 to inhibit the translational repressor 4E-binding protein 1 (4E-BP1). Here, we establish that the HSV-1 kinase Us3 masquerades as Akt to activate mTORC1. Remarkably, Us3 displays no sequence homology with the cellular kinase Akt, yet directly phosphorylates tuberous sclerosis complex 2 (TSC2) on the same sites as Akt. TSC2 depletion rescued Us3-deficient virus replication, establishing that Us3 enhances replication by phosphorylating TSC2 to constitutively activate mTORC1, effectively bypassing S6K-mediated feedback inhibition. Moreover, Us3 stimulated Akt substrate phosphorylation in infected cells, including FOXO1 and GSK3. Thus, HSV-1 encodes an Akt surrogate with overlapping substrate specificity to activate mTORC1, stimulating translation and virus replication. This establishes Us3 as a unique viral kinase with promising drug development potential.

Key Words: Translational control • herpesvirus replication • viral kinase • mTOR activation • Akt signaling

Received for publication August 4, 2010. Accepted for publication October 13, 2010.

7 Corresponding author.

E-MAIL ian.mohr{at}med.nyu.edu; FAX (212) 263-8276.

Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.1978310.

Supplemental material is available at http://www.genesdev.org.

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