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

Mamrosh JL, Lee JM, Wagner M, Stambrook PJ, Whitby RJ, Sifers RN, Wu SP, Tsai MJ, Demayo FJ, Moore DD - Elife (2014)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, United States.

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- 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- mice also cannot resolve ER stress, and restoring Plk3 expression in Lrh-1- 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.

No MeSH data available.


Related in: MedlinePlus

Loss of Lrh-1 does not result in loss of UPR target genes in response to stress.Relative expression by quantitative PCR for genes dependent on each of the three UPR pathways. RNA was collected at designated timepoints for control and Lrh-1LKO mice treated with vehicle or 1 mg/kg tunicamycin (TM) (n=3-6). Data was normalized to Tbp expression.DOI:http://dx.doi.org/10.7554/eLife.01694.004
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fig1s1: Loss of Lrh-1 does not result in loss of UPR target genes in response to stress.Relative expression by quantitative PCR for genes dependent on each of the three UPR pathways. RNA was collected at designated timepoints for control and Lrh-1LKO mice treated with vehicle or 1 mg/kg tunicamycin (TM) (n=3-6). Data was normalized to Tbp expression.DOI:http://dx.doi.org/10.7554/eLife.01694.004

Mentions: The hepatic lipid accumulation phenotype observed in Lrh-1LKO mice is identical to that observed in mice lacking any of the three UPR branches following TM treatment, suggesting that there could be a significant deficit in one or more of these pathways in our Lrh-1LKO mice. Thus, we assessed the nuclear accumulation of UPR transcription factors that represent the most downstream effector of each branch. In contrast to our expectation of a UPR deficiency, we observed comparable nuclear accumulation of downstream transcription factors for all three UPR branches in response to ER stress in both control and Lrh-1LKO mice, suggesting that all three branches were functional (Figure 1G). Target genes dependent on each of the three UPR pathways were similarly induced following TM stress in both control and Lrh-1LKO mice, confirming that XBP-1, ATF6, and ATF4 were transcriptionally active in addition to being nuclear localized in Lrh-1LKO mice (Figure 1—figure supplement 1). Importantly, however, we observed sustained signaling of these in Lrh-1LKO mice, indicating that ER stress could not be resolved in Lrh-1LKO mice despite a functional UPR (Figure 1E).


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

Mamrosh JL, Lee JM, Wagner M, Stambrook PJ, Whitby RJ, Sifers RN, Wu SP, Tsai MJ, Demayo FJ, Moore DD - Elife (2014)

Loss of Lrh-1 does not result in loss of UPR target genes in response to stress.Relative expression by quantitative PCR for genes dependent on each of the three UPR pathways. RNA was collected at designated timepoints for control and Lrh-1LKO mice treated with vehicle or 1 mg/kg tunicamycin (TM) (n=3-6). Data was normalized to Tbp expression.DOI:http://dx.doi.org/10.7554/eLife.01694.004
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3987120&req=5

fig1s1: Loss of Lrh-1 does not result in loss of UPR target genes in response to stress.Relative expression by quantitative PCR for genes dependent on each of the three UPR pathways. RNA was collected at designated timepoints for control and Lrh-1LKO mice treated with vehicle or 1 mg/kg tunicamycin (TM) (n=3-6). Data was normalized to Tbp expression.DOI:http://dx.doi.org/10.7554/eLife.01694.004
Mentions: The hepatic lipid accumulation phenotype observed in Lrh-1LKO mice is identical to that observed in mice lacking any of the three UPR branches following TM treatment, suggesting that there could be a significant deficit in one or more of these pathways in our Lrh-1LKO mice. Thus, we assessed the nuclear accumulation of UPR transcription factors that represent the most downstream effector of each branch. In contrast to our expectation of a UPR deficiency, we observed comparable nuclear accumulation of downstream transcription factors for all three UPR branches in response to ER stress in both control and Lrh-1LKO mice, suggesting that all three branches were functional (Figure 1G). Target genes dependent on each of the three UPR pathways were similarly induced following TM stress in both control and Lrh-1LKO mice, confirming that XBP-1, ATF6, and ATF4 were transcriptionally active in addition to being nuclear localized in Lrh-1LKO mice (Figure 1—figure supplement 1). Importantly, however, we observed sustained signaling of these in Lrh-1LKO mice, indicating that ER stress could not be resolved in Lrh-1LKO mice despite a functional UPR (Figure 1E).

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, United States.

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- 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- mice also cannot resolve ER stress, and restoring Plk3 expression in Lrh-1- 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.

No MeSH data available.


Related in: MedlinePlus