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 N. McClintick, Tracy G. Anthony, Ronald C. Wek

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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 (US)
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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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. N., Anthony, T. G., & Wek, R. C. (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