IRE1α-dependent decay of CReP/Ppp1r15b mRNA increases eukaryotic initiation factor 2α phosphorylation and suppresses protein synthesis

Jae Seon So, Sungyun Cho, Sang Hyun Min, Scot R. Kimball, Ann Hwee Lee

Research output: Contribution to journalArticlepeer-review

15 Scopus citations

Abstract

The unfolded protein response (UPR) regulates endoplasmic reticulum (ER) homeostasis and protects cells from ER stress. IRE1α is a central regulator of the UPR that activates the transcription factor XBP1s through an unconventional splicing mechanism using its endoribonuclease activity. IRE1α also cleaves certain mRNAs containing XBP1-like secondary structures to promote the degradation of these mRNAs, a process known as regulated IRE1α-dependent decay (RIDD). We show here that the mRNA of CReP/Ppp1r15b, a regulatory subunit of eukaryotic translation initiation factor 2α (eIF2α) phosphatase, is a RIDD substrate. eIF2α plays a central role in the integrated stress response by mediating the translational attenuation to decrease the stress level in the cell. CReP expression was markedly suppressed in XBP1-deficient mice livers due to hyperactivated IRE1α. Decreased CReP expression caused the induction of eIF2α phosphorylation and the attenuation of protein synthesis in XBP1- deficient livers. ER stress also suppressed CReP expression in an IRE1α-dependent manner, which increased eIF2α phosphorylation and consequently attenuated protein synthesis. Taken together, the results of our study reveal a novel function of IRE1α in the regulation of eIF2α phosphorylation and the translational control.

Original languageEnglish (US)
Pages (from-to)2761-2770
Number of pages10
JournalMolecular and cellular biology
Volume35
Issue number16
DOIs
StatePublished - 2015

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cell Biology

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