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 eIF2 alpha. Following ER stress induction, loss of Crbn delayed dephosphorylation of eIF2 alpha, while reconstitution of Crbn reversed enhanced phosphorylation of PERK and eIF2 alpha. Lastly, we found that activation of the PERK/eIF2 alpha 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. (C) 2015 Elsevier Inc. All rights reserved.