title: Depletion of the cereblon gene activates the unfolded protein response and protects cells from ER stress-induced cell death.
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.
authors.affiliation: School of Life Sciences and Cell Dynamics Research Center and National Leading Research Laboratory, Gwangju Institute Science and Technology (GIST), Gwangju 500-712, Republic of Korea; Department of Molecular Genetics, University of Texas South Western Medical Center, Dallas, TX 75390-9046, USA.
authors.forename: Kwang Min
authors.initials: KM
authors.lastname: Lee
authors.affiliation: School of Life Sciences and Cell Dynamics Research Center and National Leading Research Laboratory, Gwangju Institute Science and Technology (GIST), Gwangju 500-712, Republic of Korea.
authors.forename: Seung-Joo
authors.initials: SJ
authors.lastname: Yang
authors.affiliation: Asan Institute for Life Sciences, Asan Medical Center, Seoul 138-736, Republic of Korea.
authors.forename: Sojung
authors.initials: S
authors.lastname: Park
authors.affiliation: Department of Pathology, Chonnam National University Medical School, Gwangju 501-757, Republic of Korea.
authors.forename: Yoo Duk
authors.initials: YD
authors.lastname: Choi
authors.affiliation: Division of Meridian and Structural Medicine, School of Korean Medicine, Pusan National University, Yangsan, Gyeongnam, Republic of Korea.
authors.forename: Hwa Kyoung
authors.initials: HK
authors.lastname: Shin
authors.affiliation: Asan Institute for Life Sciences, Asan Medical Center, Seoul 138-736, Republic of Korea; Department of Medicine, University of Ulsan College of Medicine, Seoul 138-736, Republic of Korea.
authors.forename: Jhang Ho
authors.initials: JH
authors.lastname: Pak
authors.affiliation: School of Life Sciences and Cell Dynamics Research Center and National Leading Research Laboratory, Gwangju Institute Science and Technology (GIST), Gwangju 500-712, Republic of Korea. Electronic address: cspark@gist.ac.kr.
authors.forename: Chul-Seung
authors.initials: CS
authors.lastname: Park
authors.affiliation: Asan Institute for Life Sciences, Asan Medical Center, Seoul 138-736, Republic of Korea; Department of Medicine, University of Ulsan College of Medicine, Seoul 138-736, Republic of Korea. Electronic address: ik.kim@amc.seoul.kr.
authors.forename: Inki
authors.initials: I
authors.lastname: Kim
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D002545:Brain Ischemia / Q000235:genetics / Q000473:pathology; D016923:Cell Death / Q000235:genetics; D002478:Cells, Cultured; D059865:Endoplasmic Reticulum Stress / Q000235:genetics / Q000502:physiology*; D004789:Enzyme Activation; D005347:Fibroblasts / Q000166:cytology / Q000502:physiology; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D010100:Oxygen / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D056811:Unfolded Protein Response / Q000235:genetics*; D019892:eIF-2 Kinase / Q000378:metabolism
chemical_list: D055372:AMP-Activated Protein Kinases; D048868:Adaptor Proteins, Signal Transducing; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D010100:Oxygen; D017346:Protein Serine-Threonine Kinases; D019892:eIF-2 Kinase; C549921:Crbn protein, mouse; C486556:Ern2 protein, mouse; C531557:eIF2alpha kinase, mouse
keywords: AMP-activated kinase (AMPK); Cereblon; Endoplasmic reticulum stress (ER stress); Gene knockout; Stress response; Unfolded protein response (UPR)