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J. Virol. doi:10.1128/JVI.01063-07
Copyright (c) 2007, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Suppression of Viral Replication by Stress-inducible GADD34 via the mTOR Pathway

Department of Clinical Laboratory Medicine and; Department of Microbiology, Central Research Laboratory, Shiga University of Medical Science, Shiga 520-2192, Japan; Department of Immunology, Nagoya University School of Medicine, Nagoya 466-8550, Japan; Department of Pathology, Juntendo University, Tokyo 113-8412, Japan; PRESTO, Japan Science and Technology Agency, Saitama 332-0012, Japan

^* To whom correspondence should be addressed. Email: hirokazu{at}belle.shiga-med.ac.jp.

	Abstract

GADD34 is a protein induced by a variety of stressors, including DNA damage, heat shock, nutrient deprivation, energy depletion, and endoplasmic reticulum stress. Here, we demonstrated that GADD34 induced by vesicular stomatitis virus (VSV) infection suppressed viral replication in wild-type (WT) mouse embryo fibroblasts (MEFs), whereas replication was enhanced in GADD34-deficient (KO) MEFs. Enhanced viral replication in GADD34-KO MEFs was reduced by retroviral gene-rescue of GADD34. The level of VSV protein expression in GADD34-KO MEFs was significantly higher than that in WT MEFs. Neither phosphorylation of eIF2 nor cellular protein synthesis was correlated with viral replication in GADD34-KO MEFs. On the other hand, phosphorylation of S6 and 4EBP1, proteins downstream of mTOR, was suppressed by VSV infection in WT MEFs, but not in GADD34-KO MEFs. GADD34 was able to associate with TSC1/2 and dephosphorylate TSC2 at Thr1462. VSV replication was higher in TSC2-null cells than in TSC2-expressing cells, and constitutively active Akt enhanced VSV replication. On the other hand, rapamycin, an mTOR inhibitor, significantly suppressed VSV replication in GADD34-KO MEFs. These findings demonstrate that GADD34 induced by VSV infection suppresses viral replication via mTOR pathway inhibition, indicating that crosstalk between stress-inducible GADD34 and the mTOR signaling pathway plays a critical role in anti-viral defense.