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PMID: 15930128 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

Importance of eIF2alpha phosphorylation and stress granule assembly in alphavirus translation regulation.

Molecular biology of the cell ·Vol. 16 ·No. 8 ·2005-08-00 ·Pages 3753-63

McInerney GM, Kedersha NL, Kaufman RJ, Anderson P, Liljeström P

Abstract

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 2alpha subunit (eIF2alpha). Infection of mouse embryo fibroblasts (MEFs) expressing a nonphosphorylatable mutant of eIF2alpha 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 eIF2alpha 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 eIF2alpha 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.

MeSH Terms
Alphavirus/genetics Animals Cell Line Eukaryotic Initiation Factor-2/genetics,metabolism Fibroblasts Gene Expression Regulation, Viral Mice Phosphorylation Phosphoserine/metabolism Protein Biosynthesis RNA, Viral/genetics,metabolism Time Factors
Chemicals
Eukaryotic Initiation Factor-2 RNA, Viral Phosphoserine
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
McInerney Gerald M
Microbiology and Tumour Biology Centre, Karolinska Institute, Stockholm 171 77, Sweden. gerald.mcinerney@mtc.ki.se
Kedersha Nancy L
Kaufman Randal J
Anderson Paul
Liljeström Peter
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Article Info
Journal
Molecular biology of the cell
Abbr.
Mol Biol Cell
ISSN
1059-1524
DOI
10.1091/mbc.e05-02-0124
Email
gerald.mcinerney@mtc.ki.se
Published
2005-08-00
Epub
2005-00-01
Pages
3753-63
Language
English
Region
United States
NLM ID
9201390
PMCID
PMC1182313
Subset
IM
Grants
NIAID NIH HHS · R56 AI033600 · United States
NIAID NIH HHS · R01 AI033600 · United States
NIAID NIH HHS · AI-50167 · United States
NIAID NIH HHS · AI-33600 · United States
NIAID NIH HHS · R01 AI050167 · United States
External Links
PubMed source DOI: 10.1091/mbc.e05-02-0124 PMC Full Text View journal details
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