Selective mRNA translation during eIF2 phosphorylation induces expression of IBTKα

Mol Biol Cell. 2014 May;25(10):1686-97. doi: 10.1091/mbc.E14-02-0704. Epub 2014 Mar 19.


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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Activating Transcription Factor 4 / genetics
  • Adaptor Proteins, Signal Transducing
  • Animals
  • Base Sequence
  • Carrier Proteins / biosynthesis
  • Carrier Proteins / genetics*
  • Caspase 3 / metabolism
  • Caspase 7 / metabolism
  • Cell Division / genetics
  • Cell Line
  • Cell Survival / genetics
  • Endoplasmic Reticulum / metabolism
  • Endoplasmic Reticulum Stress / genetics*
  • Gene Expression Regulation
  • Hep G2 Cells
  • Humans
  • Mice
  • Molecular Sequence Data
  • Open Reading Frames / genetics
  • Phosphorylation
  • Protein Biosynthesis / genetics
  • Protein Serine-Threonine Kinases / genetics*
  • Protein Serine-Threonine Kinases / metabolism
  • RNA Interference
  • RNA, Messenger / genetics
  • RNA, Small Interfering
  • Transcription Factor CHOP / genetics
  • Transcription Initiation Site
  • Transcriptional Activation / genetics
  • Unfolded Protein Response / genetics*
  • eIF-2 Kinase / genetics*


  • Adaptor Proteins, Signal Transducing
  • Atf4 protein, mouse
  • Carrier Proteins
  • Ddit3 protein, mouse
  • IBtk protein, mouse
  • RNA, Messenger
  • RNA, Small Interfering
  • Activating Transcription Factor 4
  • Transcription Factor CHOP
  • PERK kinase
  • Protein Serine-Threonine Kinases
  • eIF-2 Kinase
  • eIF2alpha kinase, mouse
  • Casp7 protein, mouse
  • Caspase 3
  • Caspase 7