Selective mRNA translation during eIF2 phosphorylation induces expression of IBTKα

Thomas D. Baird, Lakshmi Reddy Palam, Michael E. Fusakio, Jeffrey A. Willy, Christopher M. Davis, Jeanette McClintick, Tracy G. Anthony, Ronald Wek

Research output: Contribution to journalArticle

46 Citations (Scopus)

Abstract

Disruption of protein folding in the endoplasmic reticulum (ER) triggers the unfolded protein response (UPR), a transcriptional and translational control network designed to restore protein homeostasis. Central to the UPR is PKR-like ER kinase (PERK/EIF2AK3) phosphorylation of the a subunit of eIF2 (eIF2α̃P), which represses global translation coincident with preferential translation of mRNAs, such as activating transcription factor 4 (ATF4) and C/EBP-homologous protein (CHOP), that serve to implement UPR transcriptional regulation. In this study, we used sucrose gradient ultracentrifugation and a genome-wide microarray approach to measure changes in mRNA translation during ER stress. Our analysis suggests that translational efficiencies vary over a broad range during ER stress, with the majority of transcripts being either repressed or resistant to eIF2α̃P, whereas a notable cohort of key regulators are subject to preferential translation. From the latter group, we identified the α isoform of inhibitor of Bruton's tyrosine kinase (IBTKα) as being subject to both translational and transcriptional induction during eIF2α̃P in both cell lines and a mouse model of ER stress. Translational regulation of IBTKα mRNA involves stress-induced relief of two inhibitory upstream open reading frames in the 5'-leader of the transcript. Depletion of IBTKα by short hairpin RNA reduced viability of cultured cells coincident with increased caspase 3/7 cleavage, suggesting that IBTKα is a key regulator in determining cell fate during the UPR.

Original languageEnglish
Pages (from-to)1666-1675
Number of pages10
JournalMolecular Biology of the Cell
Volume25
Issue number10
DOIs
StatePublished - May 15 2014

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Unfolded Protein Response
Protein Biosynthesis
Endoplasmic Reticulum Stress
Phosphorylation
Endoplasmic Reticulum
Activating Transcription Factor 4
Transcription Factor CHOP
Caspase 7
Ultracentrifugation
Protein Folding
Caspase 3
Small Interfering RNA
Open Reading Frames
Sucrose
Cultured Cells
Protein Isoforms
Homeostasis
Genome
Cell Line
Messenger RNA

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

Baird, T. D., Palam, L. R., Fusakio, M. E., Willy, J. A., Davis, C. M., McClintick, J., ... Wek, R. (2014). Selective mRNA translation during eIF2 phosphorylation induces expression of IBTKα. Molecular Biology of the Cell, 25(10), 1666-1675. https://doi.org/10.1091/mbc.E14-02-0704

Selective mRNA translation during eIF2 phosphorylation induces expression of IBTKα. / Baird, Thomas D.; Palam, Lakshmi Reddy; Fusakio, Michael E.; Willy, Jeffrey A.; Davis, Christopher M.; McClintick, Jeanette; Anthony, Tracy G.; Wek, Ronald.

In: Molecular Biology of the Cell, Vol. 25, No. 10, 15.05.2014, p. 1666-1675.

Research output: Contribution to journalArticle

Baird, TD, Palam, LR, Fusakio, ME, Willy, JA, Davis, CM, McClintick, J, Anthony, TG & Wek, R 2014, 'Selective mRNA translation during eIF2 phosphorylation induces expression of IBTKα', Molecular Biology of the Cell, vol. 25, no. 10, pp. 1666-1675. https://doi.org/10.1091/mbc.E14-02-0704
Baird TD, Palam LR, Fusakio ME, Willy JA, Davis CM, McClintick J et al. Selective mRNA translation during eIF2 phosphorylation induces expression of IBTKα. Molecular Biology of the Cell. 2014 May 15;25(10):1666-1675. https://doi.org/10.1091/mbc.E14-02-0704
Baird, Thomas D. ; Palam, Lakshmi Reddy ; Fusakio, Michael E. ; Willy, Jeffrey A. ; Davis, Christopher M. ; McClintick, Jeanette ; Anthony, Tracy G. ; Wek, Ronald. / Selective mRNA translation during eIF2 phosphorylation induces expression of IBTKα. In: Molecular Biology of the Cell. 2014 ; Vol. 25, No. 10. pp. 1666-1675.
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