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

Elife. 2014 Apr 15:3:e01694. 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.

Keywords: ER stress; liver metabolism; nuclear receptors.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Activating Transcription Factor 2 / genetics
  • Activating Transcription Factor 2 / metabolism
  • Animals
  • Cell Death
  • Cells, Cultured
  • Endoplasmic Reticulum Stress*
  • Hepatocytes / physiology
  • Liver / physiopathology*
  • Mice
  • Mice, Knockout
  • Protein Serine-Threonine Kinases / genetics
  • Protein Serine-Threonine Kinases / metabolism
  • Receptors, Cytoplasmic and Nuclear / genetics
  • Receptors, Cytoplasmic and Nuclear / metabolism*

Substances

  • Activating Transcription Factor 2
  • Atf2 protein, mouse
  • Nr5a2 protein, mouse
  • Receptors, Cytoplasmic and Nuclear
  • Plk3 protein, mouse
  • Protein Serine-Threonine Kinases