Abstract
The orphan nuclear receptor SHP (small heterodimer partner) is a well-known transcriptional corepressor of bile acid and lipid metabolism in the liver; however, its function in other tissues is poorly understood. Here, we report an unexpected role for SHP in the exocrine pancreas as a modulator of the endoplasmic reticulum (ER) stress response. SHP expression is induced in acinar cells in response to ER stress and regulates the protein stability of the spliced form of X-box-binding protein 1 (XBP1s), a key mediator of ER stress response. Loss of SHP reduces XBP1s protein level and transcriptional activity, which in turn attenuates the ER stress response during the fasting–feeding cycle. Consequently, SHP-deficient mice also are more susceptible to cerulein-induced pancreatitis. Mechanistically, we show that SHP physically interacts with the transactivation domain of XBP1s, thereby inhibiting the polyubiqui-tination and degradation of XBP1s by the Cullin3–SPOP (speckle-type POZ protein) E3 ligase complex. Together, our data implicate SHP in governing ER homeostasis and identify a novel posttranslational regulatory mechanism for the key ER stress response effector XBP1.
Original language | English (US) |
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Pages (from-to) | 1083-1094 |
Number of pages | 12 |
Journal | Genes and Development |
Volume | 33 |
Issue number | 15-16 |
DOIs | |
State | Published - Aug 2019 |
Keywords
- Cullin3
- ER stress
- Exocrine pancreas
- SHP
- Ubiquitination
- XBP1s
ASJC Scopus subject areas
- Genetics
- Developmental Biology