title: Synthetic embryonic lethality upon deletion of the ER cochaperone p58(IPK) and the ER stress sensor ATF6α.
abstract: The unfolded protein response (UPR) is activated as a consequence of alterations to ER homeostasis. It upregulates a group of ER chaperones and cochaperones, as well as other genes that improve protein processing within the secretory pathway. The UPR effector ATF6α augments-but is not essential for-maximal induction of ER chaperones during stress, yet its role, if any, in protecting cellular function during normal development and physiology is unknown. A systematic analysis of multiple tissues from Atf6α-/- mice revealed that all tissues examined were grossly insensitive to loss of ATF6α. However, combined deletion of ATF6α and the ER cochaperone p58(IPK) resulted in synthetic embryonic lethality. These findings reveal for the first time that an intact UPR can compensate for the genetic impairment of protein folding in the ER in vivo. The also expose a role for p58(IPK) in normal embryonic development.
authors.affiliation: Department of Anatomy and Cell Biology, University of Iowa Carver College of Medicine, Iowa City, IA 52242, United States.
authors.forename: Javier A
authors.initials: JA
authors.lastname: Gomez
authors.affiliation: Department of Anatomy and Cell Biology, University of Iowa Carver College of Medicine, Iowa City, IA 52242, United States.
authors.forename: Heather M
authors.initials: HM
authors.lastname: Tyra
authors.affiliation: Department of Anatomy and Cell Biology, University of Iowa Carver College of Medicine, Iowa City, IA 52242, United States.
authors.forename: Diane
authors.initials: D
authors.lastname: DeZwaan-McCabe
authors.affiliation: Department of Pathology, University of Iowa Carver College of Medicine, Iowa City, IA 52242, United States.
authors.forename: Alicia K
authors.initials: AK
authors.lastname: Olivier
authors.affiliation: Department of Anatomy and Cell Biology, University of Iowa Carver College of Medicine, Iowa City, IA 52242, United States; Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA 52242, United States. Electronic address: thomas-rutkowski@uiowa.edu.
authors.forename: D Thomas
authors.initials: DT
authors.lastname: Rutkowski
mesh_terms: D051702:Activating Transcription Factor 6 / Q000235:genetics / Q000502:physiology*; D000818:Animals; D020964:Embryo Loss / Q000235:genetics* / Q000473:pathology; D004622:Embryo, Mammalian / Q000378:metabolism / Q000473:pathology; D004721:Endoplasmic Reticulum / Q000378:metabolism; D059865:Endoplasmic Reticulum Stress / Q000235:genetics*; D005260:Female; D017353:Gene Deletion; D050956:HSP40 Heat-Shock Proteins / Q000235:genetics / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D018832:Molecular Chaperones / Q000235:genetics / Q000502:physiology*; D011247:Pregnancy
chemical_list: D051702:Activating Transcription Factor 6; C497112:Atf6 protein, mouse; C500846:Dnajc3 protein, mouse; D050956:HSP40 Heat-Shock Proteins; D018832:Molecular Chaperones
keywords: Chaperones; ER stress; Protein folding; Unfolded protein response