Constitutive mTORC1 activation by a herpesvirus Akt surrogate stimulates mRNA translation and viral replication
Year: 2010
Type: preprint
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.
Source: Genes & Development
DOI: 10.1101/gad.1978310
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: bronze
Awards: G1621308200, G239743816, G3084026282, G3210789970, G3761063458, Control of Translation in Herpesvirus Infected Cells - Resubmission - 1, Virus Host Interactions that Regulate Translation in Cells Infected with HSV-1, Infectious Disease and Basic Microbiological Mechanisms., UL34 and herpes simplex virus envelopment, G9000107337, G9000170123
OpenAlex ID: W2119628526