Article
- The EMBO Journal (2005) 24, 1211 - 1221
- doi:10.1038/sj.emboj.7600597
Published online: 3 March 2005
Subject Categories:
Adenoviral proteins mimic nutrient/growth signals to activate the mTOR pathway for viral replication
Clodagh O'Shea1, Kristina Klupsch1,ab, Serah Choi1,b, Bridget Bagus1, Conrado Soria1, Jerry Shen2, Frank McCormick1 and David Stokoe1
- Cancer Research Institute, University of California, San Francisco, CA, USA
- Onyx Pharmaceuticals, Richmond, CA, USA
Correspondence to:
Clodagh O'Shea, UCSF Cancer Center, 2340 Sutter Street, Box 0128, San Francisco, CA 94115, USA. E-mail: oshea@cc.ucsf.edu
David Stokoe, UCSF Cancer Center, 2340 Sutter Street, Box 0128, San Francisco, CA 94115, USA. Tel.: +1 415 502 2598; Fax: +1 415 502 3179; E-mail: stokoe@cc.ucsf.edu
aPresent address: Cancer Research UK, 44 Lincolns Inn Fields, London WC2A 3PX, UK
bThese two authors contributed equally to this work
Received 10 December 2004; Accepted 3 February 2005
Abstract
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.
Keywords:
- adenovirus,
- mTOR,
- nutrients,
- PI3-kinase,
- PP2A
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