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

Genes Dev. 2010 Dec 1;24(23):2627-39. doi: 10.1101/gad.1978310.


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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism
  • Cell Cycle Proteins
  • Cell Line
  • Cell Line, Tumor
  • Enzyme Activation / physiology*
  • Eukaryotic Initiation Factor-4F / metabolism
  • Gene Expression Regulation, Viral*
  • HEK293 Cells
  • Herpes Simplex / physiopathology
  • Herpes Simplex / virology*
  • Herpesvirus 1, Human / enzymology
  • Herpesvirus 1, Human / metabolism*
  • Humans
  • Phosphoproteins / metabolism
  • Phosphorylation
  • Protein Serine-Threonine Kinases / metabolism
  • Proto-Oncogene Proteins c-akt / metabolism*
  • RNA, Messenger / metabolism
  • RNA, Viral / metabolism
  • Signal Transduction
  • Transcription Factors / metabolism*
  • Tuberous Sclerosis Complex 2 Protein
  • Tumor Suppressor Proteins / metabolism
  • Viral Proteins / metabolism
  • Virus Replication*


  • Adaptor Proteins, Signal Transducing
  • CRTC1 protein, human
  • Cell Cycle Proteins
  • EIF4EBP1 protein, human
  • Eukaryotic Initiation Factor-4F
  • Phosphoproteins
  • RNA, Messenger
  • RNA, Viral
  • TSC2 protein, human
  • Transcription Factors
  • Tuberous Sclerosis Complex 2 Protein
  • Tumor Suppressor Proteins
  • Viral Proteins
  • Protein Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • US3 protein, Human herpesvirus 1