Depletion of the cereblon gene activates the unfolded protein response and protects cells from ER stress-induced cell death

Kwang Min Lee, Seung Joo Yang, Sojung Park, Yoo Duk Choi, Hwa Kyoung Shin, Jhang Ho Pak, Chul Seung Park, Inki Kim

Research output: Contribution to journalArticlepeer-review

10 Scopus citations

Abstract

Previous studies showed that cereblon (CRBN) binds to various cellular target proteins, implying that CRBN regulates a wide range of cell responses. In this study, we found that deletion of the Crbn gene desensitized mouse embryonic fibroblast cells to various cell death-promoting stimuli, including endoplasmic reticulum stress inducers. Mechanistically, deletion of Crbn activates pathways involved in the unfolded protein response prior to ER stress induction. Loss of Crbn activated PKR-like ER kinase (PERK) with enhanced phosphorylation of eIF2α. Following ER stress induction, loss of Crbn delayed dephosphorylation of eIF2α, while reconstitution of Crbn reversed enhanced phosphorylation of PERK and eIF2α. Lastly, we found that activation of the PERK/eIF2α pathway following Crbn deletion is caused by activation of AMP-activated protein kinase (AMPK). We propose that CRBN plays a role in cellular stress signaling, including the unfolded protein response, by controlling the activity of AMPK.

Original languageEnglish
Pages (from-to)34-39
Number of pages6
JournalBiochemical and Biophysical Research Communications
Volume458
Issue number1
DOIs
StatePublished - 27 Feb 2015

Keywords

  • AMP-activated kinase (AMPK)
  • Cereblon
  • Endoplasmic reticulum stress (ER stress)
  • Gene knockout
  • Stress response
  • Unfolded protein response (UPR)

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