Journal article
Constitutive mTORC1 activation by a herpesvirus Akt surrogate stimulates mRNA translation and viral replication
Genes & development, Vol.24(23), pp.2627-2639
12/01/2010
DOI: 10.1101/gad.1978310
PMCID: PMC2994037
PMID: 21123650
Abstract
All viruses require cellular ribosomes to translate their mRNAs. Viruses producing methyl-7 (m
7
) 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.
Details
- Title: Subtitle
- Constitutive mTORC1 activation by a herpesvirus Akt surrogate stimulates mRNA translation and viral replication
- Creators
- Uyanga Chuluunbaatar - Center for Health Informatics and Bioinformatics, New York University School of Medicine, New York, New York, 10016, USARichard Roller - Center for Health Informatics and Bioinformatics, New York University School of Medicine, New York, New York, 10016, USAMorris E Feldman - Center for Health Informatics and Bioinformatics, New York University School of Medicine, New York, New York, 10016, USAStuart Brown - Center for Health Informatics and Bioinformatics, New York University School of Medicine, New York, New York, 10016, USAKevan M Shokat - Center for Health Informatics and Bioinformatics, New York University School of Medicine, New York, New York, 10016, USAIan Mohr - Center for Health Informatics and Bioinformatics, New York University School of Medicine, New York, New York, 10016, USA
- Resource Type
- Journal article
- Publication Details
- Genes & development, Vol.24(23), pp.2627-2639
- Publisher
- Cold Spring Harbor Laboratory Press
- DOI
- 10.1101/gad.1978310
- PMID
- 21123650
- PMCID
- PMC2994037
- ISSN
- 0890-9369
- eISSN
- 1549-5477
- Language
- English
- Date published
- 12/01/2010
- Academic Unit
- Microbiology and Immunology
- Record Identifier
- 9984002398602771
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