Genes & development, 2010-12, Vol.24 (23), p.2627-2639
2010
Details
- Autor(en) / Beteiligte
- Titel
- Constitutive mTORC1 activation by a herpesvirus Akt surrogate stimulates mRNA translation and viral replication
- Ist Teil von
- Genes & development, 2010-12, Vol.24 (23), p.2627-2639
- Ort / Verlag
- United States: Cold Spring Harbor Laboratory Press
- Erscheinungsjahr
- 2010
- Link zum Volltext
- Quelle
- Free E-Journal (出版社公開部分のみ）
- Beschreibungen/Notizen
- 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.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 0890-9369eISSN: 1549-5477DOI: 10.1101/gad.1978310Titel-ID: cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_2994037
- Format
- –
- Schlagworte
- Adaptor Proteins, Signal Transducing - metabolism, 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, Herpes simplex virus 1, Herpesvirus, Herpesvirus 1, Human - enzymology, Herpesvirus 1, Human - metabolism, Humans, Phosphoproteins - metabolism, Phosphorylation, Protein-Serine-Threonine Kinases - metabolism, Proto-Oncogene Proteins c-akt - metabolism, Research Paper, 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