title: Nuclear receptor LRH-1/NR5A2 is required and targetable for liver endoplasmic reticulum stress resolution.
abstract: Chronic endoplasmic reticulum (ER) stress results in toxicity that contributes to multiple human disorders. We report a stress resolution pathway initiated by the nuclear receptor LRH-1 that is independent of known unfolded protein response (UPR) pathways. Like mice lacking primary UPR components, hepatic Lrh-1-null mice cannot resolve ER stress, despite a functional UPR. In response to ER stress, LRH-1 induces expression of the kinase Plk3, which phosphorylates and activates the transcription factor ATF2. Plk3-null mice also cannot resolve ER stress, and restoring Plk3 expression in Lrh-1-null cells rescues ER stress resolution. Reduced or heightened ATF2 activity also sensitizes or desensitizes cells to ER stress, respectively. LRH-1 agonist treatment increases ER stress resistance and decreases cell death. We conclude that LRH-1 initiates a novel pathway of ER stress resolution that is independent of the UPR, yet equivalently required. Targeting LRH-1 may be beneficial in human disorders associated with chronic ER stress. DOI: http://dx.doi.org/10.7554/eLife.01694.001.
authors.affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, United States.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Mamrosh
authors.forename: Jae Man
authors.initials: JM
authors.lastname: Lee
authors.forename: Martin
authors.initials: M
authors.lastname: Wagner
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Stambrook
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Whitby
authors.forename: Richard N
authors.initials: RN
authors.lastname: Sifers
authors.forename: San-Pin
authors.initials: SP
authors.lastname: Wu
authors.forename: Ming-Jer
authors.initials: MJ
authors.lastname: Tsai
authors.forename: Francesco J
authors.initials: FJ
authors.lastname: Demayo
authors.forename: David D
authors.initials: DD
authors.lastname: Moore
mesh_terms: D051698:Activating Transcription Factor 2 / Q000235:genetics / Q000378:metabolism; D000818:Animals; D016923:Cell Death; D002478:Cells, Cultured; D059865:Endoplasmic Reticulum Stress; D022781:Hepatocytes / Q000502:physiology; D008099:Liver / Q000503:physiopathology*; D051379:Mice; D018345:Mice, Knockout; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism*
chemical_list: D051698:Activating Transcription Factor 2; C497106:Atf2 protein, mouse; C431936:Nr5a2 protein, mouse; D018160:Receptors, Cytoplasmic and Nuclear; C093328:Plk3 protein, mouse; D017346:Protein Serine-Threonine Kinases
keywords: ER stress; liver metabolism; nuclear receptors
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