Constitutive mTORC1 activation by a herpesvirus Akt surrogate stimulates mRNA translation and viral replication.
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.
Department of Microbiology, New York University School of Medicine, New York, 10016, USA.
Uyanga
U
Chuluunbaatar
Richard
R
Roller
Morris E
ME
Feldman
Stuart
S
Brown
Kevan M
KM
Shokat
Ian
I
Mohr
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D018797:Cell Cycle Proteins; D002460:Cell Line; D045744:Cell Line, Tumor; D004789:Enzyme Activation / Q000502:physiology*; D039562:Eukaryotic Initiation Factor-4F / Q000378:metabolism; D015967:Gene Expression Regulation, Viral; D057809:HEK293 Cells; D006561:Herpes Simplex / Q000503:physiopathology / Q000821:virology*; D018259:Herpesvirus 1, Human / Q000201:enzymology / Q000378:metabolism*; D006801:Humans; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D012367:RNA, Viral / Q000378:metabolism; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism*; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D014764:Viral Proteins / Q000378:metabolism; D014779:Virus Replication
D048868:Adaptor Proteins, Signal Transducing; C500984:CRTC1 protein, human; D018797:Cell Cycle Proteins; C087000:EIF4EBP1 protein, human; D039562:Eukaryotic Initiation Factor-4F; D010750:Phosphoproteins; D012333:RNA, Messenger; D012367:RNA, Viral; C000624653:TSC2 protein, human; D014157:Transcription Factors; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; D014764:Viral Proteins; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; C095207:US3 protein, Human herpesvirus 1