title: Fine tuning of the UPR by the ubiquitin ligases Siah1/2.
abstract: The endoplasmic reticulum (ER) responds to changes in intracellular homeostasis through activation of the unfolded protein response (UPR). Yet, it is not known how UPR-signaling coordinates adaptation versus cell death. Previous studies suggested that signaling through PERK/ATF4 is required for cell death. We show that high levels of ER stress (i.e., ischemia-like conditions) induce transcription of the ubiquitin ligases Siah1/2 through the UPR transducers PERK/ATF4 and IRE1/sXBP1. In turn, Siah1/2 attenuates proline hydroxylation of ATF4, resulting in its stabilization, thereby augmenting ER stress output. Conversely, ATF4 activation is reduced upon Siah1/2 KD in cultured cells, which attenuates ER stress-induced cell death. Notably, Siah1a(+/-)::Siah2(-/-) mice subjected to neuronal ischemia exhibited smaller infarct volume and were protected from ischemia-induced death, compared with the wild type (WT) mice. In all, Siah1/2 constitutes an obligatory fine-tuning mechanism that predisposes cells to death under severe ER stress conditions.
authors.affiliation: Tumor Initiation and Maintenance Program, Cancer Center, Sanford-Burnham Medical Research Institute, La Jolla, California, United States of America.
authors.forename: Marzia
authors.initials: M
authors.lastname: Scortegagna
authors.affiliation: Tumor Initiation and Maintenance Program, Cancer Center, Sanford-Burnham Medical Research Institute, La Jolla, California, United States of America.
authors.forename: Hyungsoo
authors.initials: H
authors.lastname: Kim
authors.affiliation: Proteomics Facility, Sanford-Burnham Medical Research Institute, La Jolla, California, United States of America.
authors.forename: Jian-Liang
authors.initials: JL
authors.lastname: Li
authors.affiliation: Department of Pediatrics, University of California, San Diego, La Jolla, California, United States of America.
authors.forename: Hang
authors.initials: H
authors.lastname: Yao
authors.affiliation: Proteomics Facility, Sanford-Burnham Medical Research Institute, La Jolla, California, United States of America.
authors.forename: Laurence M
authors.initials: LM
authors.lastname: Brill
authors.affiliation: Degenerative Diseases Program, Sanford-Burnham Medical Research Institute, La Jolla, California, United States of America.
authors.forename: Jaeseok
authors.initials: J
authors.lastname: Han
authors.affiliation: Tumor Initiation and Maintenance Program, Cancer Center, Sanford-Burnham Medical Research Institute, La Jolla, California, United States of America.
authors.forename: Eric
authors.initials: E
authors.lastname: Lau
authors.affiliation: Department of Biochemistry and Molecular Biology, The University of Melbourne, Parkville, Victoria, Australia; Department of Pathology, The University of Melbourne, Parkville, Victoria, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia; Cancer Genomics and Genetics, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia.
authors.forename: David
authors.initials: D
authors.lastname: Bowtell
authors.affiliation: Department of Pediatrics, University of California, San Diego, La Jolla, California, United States of America.
authors.forename: Gabriel
authors.initials: G
authors.lastname: Haddad
authors.affiliation: Degenerative Diseases Program, Sanford-Burnham Medical Research Institute, La Jolla, California, United States of America.
authors.forename: Randal J
authors.initials: RJ
authors.lastname: Kaufman
authors.affiliation: Tumor Initiation and Maintenance Program, Cancer Center, Sanford-Burnham Medical Research Institute, La Jolla, California, United States of America.
authors.forename: Ze'ev A
authors.initials: ZA
authors.lastname: Ronai
mesh_terms: D000818:Animals; D016466:CHO Cells; D002478:Cells, Cultured; D006224:Cricetinae; D003412:Cricetulus; D004721:Endoplasmic Reticulum / Q000378:metabolism; D004789:Enzyme Activation; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism*; D051379:Mice; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D013312:Stress, Physiological; D014158:Transcription, Genetic; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D056811:Unfolded Protein Response
chemical_list: D007527:Isoenzymes; D012333:RNA, Messenger; C533102:Siah2 protein, mouse; D044767:Ubiquitin-Protein Ligases