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

Author
item MAMROSH, JENNIFER - Baylor College Of Medicine
item LEE, JAE MAN - Baylor College Of Medicine
item WAGNER, MARTIN - Baylor College Of Medicine
item STAMBROOK, PETER - University Of Cincinnati
item WHITBY, RICHARD - University Of Southampton
item SIFERS, RICHARD - Baylor College Of Medicine
item WU, SAN-PIN - Baylor College Of Medicine
item TSAI, MING-JER - Baylor College Of Medicine
item DEMAYO, FRANCESCO - Baylor College Of Medicine
item MOORE, DAVID - Children'S Nutrition Research Center (CNRC)

Submitted to: eLife
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 2/27/2014
Publication Date: 4/15/2014
Citation: Mamrosh, J.L., Lee, J., Wagner, M., Stambrook, P.J., Whitby, R.J., Sifers, R.N., Wu, S., Tsai, M., Demayo, F.J., Moore, D.D. 2014. Nuclear receptor LRH-1/NR5A2 is required and targetable for liver endoplasmic reticulum stress resolution. eLife. 3:e01694.

Interpretive Summary: Cells can protect themselves against different kinds of stress. A pathway that has been extensively studied detects disorganized proteins that are not functioning correctly, which can occur in cells that do not have proper nutrients. This pathway, called the unfolded protein response, can be activated by either too much or too little of particular nutrients, including fats and the amino acid components of proteins. The unfolded protein response restores proper protein organization and function. We found that a specific protein called LRH-1 is a new contributor to this response. LRH-1 is required for proper activity of the unfolded protein response, and increasing LRH-1 activity allows the cell to respond effectively to higher levels of disorganized protein stress. A better understanding of the function of LRH-1 may allow us to maintain proper health under stressful conditions, including poor nutrient status.

Technical 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.