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
- 1Department of Microbiology, New York University School of Medicine, New York, New York 10016, USA;
- 2New York University Cancer Institute, New York University School of Medicine, New York, New York 10016, USA;
- 3Department of Microbiology, University of Iowa, Iowa City, Iowa 52242, USA;
- 4Howard Hughes Medical Institute, University of California at San Francisco, San Francisco, California 9143, USA;
- 5Department of Cellular and Molecular Pharmacology, University of California at San Francisco, San Francisco, California 9143, USA;
- 6Center 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.
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Footnotes
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↵7 Corresponding author.
E-MAIL ian.mohr{at}med.nyu.edu; FAX (212) 263-8276.
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Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.1978310.
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Supplemental material is available at http://www.genesdev.org.
- Received August 4, 2010.
- Accepted October 13, 2010.
- Copyright © 2010 by Cold Spring Harbor Laboratory Press
