Nuclear receptor LRH-1/NR5A2 is required and targetable for liver endoplasmic reticulum stress resolution

• Main Authors: Mamrosh, Jennifer L. (Author), Lee, Jae M. (Author), Wagner, Martin (Author), Stambrook, Peter J. (Author), Whitby, Richard J. (Author), Sifers, Richard N. (Author), Wu, San-pin (Author), Tsai, Ming-jer (Author), DeMayo, Fransesco J. (Author), Moore, David D. (Author)
• Format: Article
• Language: English
• Published: 2014-04-15.
• Subjects: Article
• Online Access: Get fulltext

 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.