Selective mRNA translation during eIF2 phosphorylation induces expression of IBTKα

dc.contributor.authorBaird, Thomas D.
dc.contributor.authorPalam, Lakshmi Reddy
dc.contributor.authorFusakio, Michael E.
dc.contributor.authorWilly, Jeffrey A.
dc.contributor.authorDavis, Christopher M.
dc.contributor.authorMcClintick, Jeanette N.
dc.contributor.authorAnthony, Tracy G.
dc.contributor.authorWek, Ronald C.
dc.contributor.departmentBiochemistry and Molecular Biology, School of Medicine
dc.date.accessioned2025-04-14T10:30:13Z
dc.date.available2025-04-14T10:30:13Z
dc.date.issued2014
dc.description.abstractDisruption 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.versionFinal published version
dc.identifier.citationBaird 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.urihttps://hdl.handle.net/1805/47031
dc.language.isoen_US
dc.publisherAmerican Society for Cell Biology
dc.relation.isversionof10.1091/mbc.E14-02-0704
dc.relation.journalMolecular Biology of the Cell
dc.rightsAttribution-NonCommercial-ShareAlike 4.0 Internationalen
dc.rights.urihttp://creativecommons.org/licenses/by-nc-sa/4.0/
dc.sourcePMC
dc.subjectProtein serine-threonine kinases
dc.subjectCell division
dc.subjectPhosphorylation
dc.subjectEndoplasmic reticulum stress
dc.titleSelective mRNA translation during eIF2 phosphorylation induces expression of IBTKα
dc.typeArticle
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