The alpha subunit of eukaryotic initiation factor 2B (eIF2B) is required for eIF2-mediated translational suppression of vesicular stomatitis virus

Rachel Elsby, Joshua F. Heiber, Peter Reid, Scot R. Kimball, Graham D. Pavitt, Glen N Barber

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

Eukaryotic translation initiation factor 2B (eIF2B) is a heteropentameric guanine nucleotide exchange factor that converts protein synthesis initiation factor 2 (eIF2) from a GDP-bound form to the active eIF2-GTP complex. Cellular stress can repress translation initiation by activating kinases capable of phosphorylating the alpha subunit of eIF2 (eIF2α), which sequesters eIF2B to prevent exchange activity. Previously, we demonstrated that tumor cells are sensitive to viral replication, possibly due to the occurrence of defects in eIF2B that overcome the inhibitory effects of eIF2α phosphorylation. To extend this analysis, we have investigated the importance of eIF2Bα function and report that this subunit can functionally substitute for its counterpart, GCN3, in yeast. In addition, a variant of mammalian eIF2Bα harboring a point mutation (T41A) was able overcome translational inhibition invoked by amino acid depravation, which activates Saccharomyces cerevisiae GCN2 to phosphorylate the yeast eIF2α homolog SUI2. Significantly, we also demonstrate that the loss of eIF2Bα, or the expression of the T41A variant in mammalian cells, is sufficient to neutralize the consequences of eIF2α phosphorylation and render normal cells susceptible to virus infection. Our data emphasize the importance of eIF2Bα in mediating the eIF2 kinase translation-inhibitory activity and may provide insight into the complex nature of viral oncolysis.

Original languageEnglish
Pages (from-to)9716-9725
Number of pages10
JournalJournal of Virology
Volume85
Issue number19
DOIs
StatePublished - Oct 1 2011

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Eukaryotic Initiation Factor-2B
Vesiculovirus
Vesicular Stomatitis
translation (genetics)
Viruses
phosphorylation
phosphotransferases (kinases)
yeasts
point mutation
virus replication
Saccharomyces cerevisiae
protein synthesis
cells
Phosphotransferases
Prokaryotic Initiation Factor-2
Yeasts
Phosphorylation
viruses
amino acids
Eukaryotic Initiation Factors

ASJC Scopus subject areas

  • Immunology
  • Virology

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The alpha subunit of eukaryotic initiation factor 2B (eIF2B) is required for eIF2-mediated translational suppression of vesicular stomatitis virus. / Elsby, Rachel; Heiber, Joshua F.; Reid, Peter; Kimball, Scot R.; Pavitt, Graham D.; Barber, Glen N.

In: Journal of Virology, Vol. 85, No. 19, 01.10.2011, p. 9716-9725.

Research output: Contribution to journalArticle

Elsby, Rachel ; Heiber, Joshua F. ; Reid, Peter ; Kimball, Scot R. ; Pavitt, Graham D. ; Barber, Glen N. / The alpha subunit of eukaryotic initiation factor 2B (eIF2B) is required for eIF2-mediated translational suppression of vesicular stomatitis virus. In: Journal of Virology. 2011 ; Vol. 85, No. 19. pp. 9716-9725.
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