Selective mRNA translation during eIF2 phosphorylation induces expression of IBTKα
dc.contributor.author | Baird, Thomas D. | |
dc.contributor.author | Palam, Lakshmi Reddy | |
dc.contributor.author | Fusakio, Michael E. | |
dc.contributor.author | Willy, Jeffrey A. | |
dc.contributor.author | Davis, Christopher M. | |
dc.contributor.author | McClintick, Jeanette N. | |
dc.contributor.author | Anthony, Tracy G. | |
dc.contributor.author | Wek, Ronald C. | |
dc.contributor.department | Biochemistry and Molecular Biology, School of Medicine | |
dc.date.accessioned | 2025-04-14T10:30:13Z | |
dc.date.available | 2025-04-14T10:30:13Z | |
dc.date.issued | 2014 | |
dc.description.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 α subunit of eIF2 (eIF2α∼P), 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 eIF2α∼P, 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 eIF2α∼P 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. | |
dc.eprint.version | Final published version | |
dc.identifier.citation | Baird TD, Palam LR, Fusakio ME, et al. Selective mRNA translation during eIF2 phosphorylation induces expression of IBTKα. Mol Biol Cell. 2014;25(10):1686-1697. doi:10.1091/mbc.E14-02-0704 | |
dc.identifier.uri | https://hdl.handle.net/1805/47031 | |
dc.language.iso | en_US | |
dc.publisher | American Society for Cell Biology | |
dc.relation.isversionof | 10.1091/mbc.E14-02-0704 | |
dc.relation.journal | Molecular Biology of the Cell | |
dc.rights | Attribution-NonCommercial-ShareAlike 4.0 International | en |
dc.rights.uri | http://creativecommons.org/licenses/by-nc-sa/4.0/ | |
dc.source | PMC | |
dc.subject | Protein serine-threonine kinases | |
dc.subject | Cell division | |
dc.subject | Phosphorylation | |
dc.subject | Endoplasmic reticulum stress | |
dc.title | Selective mRNA translation during eIF2 phosphorylation induces expression of IBTKα | |
dc.type | Article |