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Constitutive mTORC1 activation by a herpesvirus Akt surrogate stimulates mRNA translation and viral replication
Morris E. Feldman4,5,
Kevan M. Shokat4,5,, and
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
All viruses require cellular ribosomes to translate their mRNAs.Viruses producing methyl-7 (m7) GTP-capped mRNAs, like HerpesSimplex Virus-1 (HSV-1), stimulate cap-dependent translationby activating mTORC1 to inhibit the translational repressor4E-binding protein 1 (4E-BP1). Here, we establish that the HSV-1kinase 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-deficientvirus replication, establishing that Us3 enhances replicationby phosphorylating TSC2 to constitutively activate mTORC1, effectivelybypassing S6K-mediated feedback inhibition. Moreover, Us3 stimulatedAkt substrate phosphorylation in infected cells, including FOXO1and GSK3. Thus, HSV-1 encodes an Akt surrogate with overlappingsubstrate specificity to activate mTORC1, stimulating translationand virus replication. This establishes Us3 as a unique viralkinase with promising drug development potential.
Hepatitis C Virus NS5A Binds to the mRNA Cap-binding Eukaryotic Translation Initiation 4F (eIF4F) Complex and Up-regulates Host Translation Initiation Machinery through eIF4E-binding Protein 1 Inactivation.
A. George, S. Panda, D. Kudmulwar, S. P. Chhatbar, S. C. Nayak, and H. H. Krishnan (2012)
J. Biol. Chem.
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Herpes Simplex Virus 1 Protein Kinase Us3 and Major Tegument Protein UL47 Reciprocally Regulate Their Subcellular Localization in Infected Cells.
A. Kato, Z. Liu, A. Minowa, T. Imai, M. Tanaka, K. Sugimoto, Y. Nishiyama, J. Arii, and Y. Kawaguchi (2011)
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The Alphaherpesvirus Serine/Threonine Kinase Us3 Disrupts Promyelocytic Leukemia Protein Nuclear Bodies.