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Vol. 16, Issue 8, 3753-3763, August 2005

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Importance of eIF2 Phosphorylation and Stress Granule Assembly in Alphavirus Translation Regulation

Gerald M. McInerney ^*, Nancy L. Kedersha , Randal J. Kaufman , Paul Anderson , and Peter Liljeström ^* 

^* Microbiology and Tumour Biology Centre, Karolinska Institute, Stockholm 171 77, Sweden; Division of Rheumatology and Immunology, Brigham and Women's Hospital, Boston, MA 02115; Howard Hughes Medical Institute, Department of Biological Chemistry, University of Michigan, Ann Arbor, MI 48109-0659; and Department of Vaccine Research, Swedish Institute for Infectious Disease Control, Stockholm 105 21, Sweden

Submitted February 14, 2005; Revised May 16, 2005; Accepted May 19, 2005
Monitoring Editor: Marvin P. Wickens

Alphavirus infection results in the shutoff of host protein synthesis in favor of viral translation. Here, we show that during Semliki Forest virus (SFV) infection, the translation inhibition is largely due to the activation of the cellular stress response via phosphorylation of eukaryotic translation initiation factor 2 subunit (eIF2). Infection of mouse embryo fibroblasts (MEFs) expressing a nonphosphorylatable mutant of eIF2 does not result in efficient shutoff, despite efficient viral protein production. Furthermore, we show that the SFV translation enhancer element counteracts the translation inhibition imposed by eIF2 phosphorylation. In wild-type MEFs, viral infection induces the transient formation of stress granules (SGs) containing the cellular TIA-1/R proteins. These SGs are disassembled in the vicinity of viral RNA replication, synchronously with the switch from cellular to viral gene expression. We propose that phosphorylation of eIF2 and the consequent SG assembly is important for shutoff to occur and that the localized SG disassembly and the presence of the enhancer aid the SFV mRNAs to elude general translational arrest.

Address correspondence to: Gerald M. McInerney (gerald.mcinerney{at}mtc.ki.se).

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