Adenoviral proteins mimic nutrient/growth signals to activate the mTOR pathway for viral replication.
Like tumor cells, DNA viruses have had to evolve mechanisms that uncouple cellular replication from the many intra- and extracellular factors that normally control it. Here we show that adenovirus encodes two proteins that activate the mammalian target of rapamycin (mTOR) for viral replication, even under nutrient/growth factor-limiting conditions. E4-ORF1 mimics growth factor signaling by activating PI3-kinase, resulting in increased Rheb.GTP loading and mTOR activation. E4-ORF4 is redundant with glucose in stimulating mTOR, does not affect Rheb.GTP levels and is the major mechanism whereby adenovirus activates mTOR in quiescent primary cells. We demonstrate that mTOR is activated through a mechanism that is dependent on the E4-ORF4 protein phosphatase 2A-binding domain. We also show that mTOR activation is required for efficient S-phase entry, independently of E2F activation, in adenovirus-infected quiescent primary cells. These data reveal that adenovirus has evolved proteins that activate the mTOR pathway, irrespective of the cellular microenvironment, and which play a requisite role in viral replication.
O'Shea
Clodagh
C
Cancer Research Institute, University of California, San Francisco, CA, USA. oshea@cc.ucsf.edu
Klupsch
Kristina
K
Choi
Serah
S
Bagus
Bridget
B
Soria
Conrado
C
Shen
Jerry
J
McCormick
Frank
F
Stokoe
David
D
D000256:Adenoviridae / Q000502:physiology*; D017504:Adenovirus E4 Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D004261:DNA Replication / Q000502:physiology; D004789:Enzyme Activation; D006801:Humans; D020559:Monomeric GTP-Binding Proteins / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D009479:Neuropeptides / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010749:Phosphoprotein Phosphatases / Q000032:analysis / Q000378:metabolism; D010766:Phosphorylation; D014176:Protein Biosynthesis; D011494:Protein Kinases / Q000378:metabolism*; D054648:Protein Phosphatase 2; D000076205:Ras Homolog Enriched in Brain Protein; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism; D016196:S Phase / Q000502:physiology; D058570:TOR Serine-Threonine Kinases; D014779:Virus Replication / Q000502:physiology*
D017504:Adenovirus E4 Proteins; D020559:Monomeric GTP-Binding Proteins; D009479:Neuropeptides; D019869:Phosphatidylinositol 3-Kinases; D010749:Phosphoprotein Phosphatases; D011494:Protein Kinases; D054648:Protein Phosphatase 2; D000076205:Ras Homolog Enriched in Brain Protein; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases; C432785:PPP2R1B protein, human; C086766:Ppp2r1b protein, mouse; C490211:RHEB protein, human; C546842:MTOR protein, human; C546843:mTOR protein, mouse