The University of Southampton
University of Southampton Institutional Repository

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

Nuclear receptor LRH-1/NR5A2 is required and targetable for liver endoplasmic reticulum stress resolution
Nuclear receptor LRH-1/NR5A2 is required and targetable for liver endoplasmic reticulum stress resolution
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.
2050-084X
1-24
Mamrosh, Jennifer L.
1010ec49-76aa-4bad-b4cd-a14b39288885
Lee, Jae M.
325233f6-2f80-4994-826f-7c9c591447a0
Wagner, Martin
8234c21b-be2d-43ce-8c1c-47fac132e9e1
Stambrook, Peter J.
385bcfa6-48d0-4af1-a4e3-b06ac4710ee6
Whitby, Richard J.
45632236-ab00-4ad0-a02d-6209043e818b
Sifers, Richard N.
f9af8ab0-b61f-49d6-8dd1-b9fb06d13e84
Wu, San-pin
8f7ae80c-0966-425f-aaf1-aa773b287223
Tsai, Ming-jer
bef6e41a-5afd-41a3-8871-f99904deac47
DeMayo, Fransesco J.
fbf5f980-1317-4494-bbc5-ee84f9c7ff32
Moore, David D.
8048cd00-ef4a-4e79-8882-4edbd525f91d
Mamrosh, Jennifer L.
1010ec49-76aa-4bad-b4cd-a14b39288885
Lee, Jae M.
325233f6-2f80-4994-826f-7c9c591447a0
Wagner, Martin
8234c21b-be2d-43ce-8c1c-47fac132e9e1
Stambrook, Peter J.
385bcfa6-48d0-4af1-a4e3-b06ac4710ee6
Whitby, Richard J.
45632236-ab00-4ad0-a02d-6209043e818b
Sifers, Richard N.
f9af8ab0-b61f-49d6-8dd1-b9fb06d13e84
Wu, San-pin
8f7ae80c-0966-425f-aaf1-aa773b287223
Tsai, Ming-jer
bef6e41a-5afd-41a3-8871-f99904deac47
DeMayo, Fransesco J.
fbf5f980-1317-4494-bbc5-ee84f9c7ff32
Moore, David D.
8048cd00-ef4a-4e79-8882-4edbd525f91d

Mamrosh, Jennifer L., Lee, Jae M., Wagner, Martin, Stambrook, Peter J., Whitby, Richard J., Sifers, Richard N., Wu, San-pin, Tsai, Ming-jer, DeMayo, Fransesco J. and Moore, David D. (2014) Nuclear receptor LRH-1/NR5A2 is required and targetable for liver endoplasmic reticulum stress resolution. eLife, 1-24. (doi:10.7554/eLife.01694).

Record type: Article

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.

Text
elife_paper_2014_01694.pdf - Version of Record
Available under License Other.
Download (5MB)

More information

Published date: 15 April 2014
Organisations: Chemistry

Identifiers

Local EPrints ID: 370268
URI: http://eprints.soton.ac.uk/id/eprint/370268
ISSN: 2050-084X
PURE UUID: 55521394-fa31-40fd-90af-7d01b80fc6e5
ORCID for Richard J. Whitby: ORCID iD orcid.org/0000-0002-9891-5502

Catalogue record

Date deposited: 28 Oct 2014 11:33
Last modified: 17 Dec 2019 02:04

Export record

Altmetrics

Contributors

Author: Jennifer L. Mamrosh
Author: Jae M. Lee
Author: Martin Wagner
Author: Peter J. Stambrook
Author: Richard N. Sifers
Author: San-pin Wu
Author: Ming-jer Tsai
Author: Fransesco J. DeMayo
Author: David D. Moore

University divisions

Download statistics

Downloads from ePrints over the past year. Other digital versions may also be available to download e.g. from the publisher's website.

View more statistics

Atom RSS 1.0 RSS 2.0

Contact ePrints Soton: eprints@soton.ac.uk

ePrints Soton supports OAI 2.0 with a base URL of http://eprints.soton.ac.uk/cgi/oai2

This repository has been built using EPrints software, developed at the University of Southampton, but available to everyone to use.

We use cookies to ensure that we give you the best experience on our website. If you continue without changing your settings, we will assume that you are happy to receive cookies on the University of Southampton website.

×