IRE1α-Dependent Decay of CReP/Ppp1r15b mRNA Increases Eukaryotic Initiation Factor 2α Phosphorylation and Suppresses Protein Synthesis. Academic Article uri icon

Overview

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.

publication date

  • June 1, 2015

Research

keywords

  • Endoribonucleases
  • Eukaryotic Initiation Factor-2
  • Protein Biosynthesis
  • Protein Phosphatase 1
  • Protein Serine-Threonine Kinases
  • RNA Stability
  • RNA, Messenger

Identity

PubMed Central ID

  • PMC4508316

Scopus Document Identifier

  • 84937841076

Digital Object Identifier (DOI)

  • 10.1126/science.1201396

PubMed ID

  • 26031337

Additional Document Info

volume

  • 35

issue

  • 16