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

Jennifer L Mamrosh,San-Pin Wu,Francesco J Demayo,Peter J Stambrook,Richard J Whitby,Martin Wagner,Ming-Jer Tsai,Richard N Sifers,David D Moore,Jae Man Lee

doi:10.7554/elife.01694

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.

Highlights

It has been estimated that close to one-third of newly synthesized proteins cannot properly fold and are subjected to rapid intracellular degradation (Schubert et al, 2000)
We observed increased TUNEL staining by 72 hr following stress in Lrh-1LKO mice, confirming that the prolonged endoplasmic reticulum (ER) stress had resulted in increased apoptosis (Figure 1C,D)
We observed little increase in staining for control cells treated with TM, suggesting that resolvable ER stress induced by TM does not result in significant protein aggregation, but observed strong staining in Lrh-1LKO cells increasing over time treated with TM (Figure 1F)

Summary

Introduction

It has been estimated that close to one-third of newly synthesized proteins cannot properly fold and are subjected to rapid intracellular degradation (Schubert et al, 2000). Both the large scale of this process and the toxicity of misfolded proteins dictate that protein folding must be tightly controlled. Especially metabolic and neurodegenerative disorders, cellular folding capacities are overwhelmed by increased protein synthesis rates and/or accumulation of abnormal proteins, resulting in ER stress-mediated cell toxicity or death (Lin et al, 2008). The UPR consists of three distinct pathways, each of which is initiated by a specific ER-bound protein that acts as a sensor for misfolded proteins. Many additional components of ER stress resolution have been identified, often with roles in maintenance of metabolic homeostasis following exposure to stress

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Conclusion