| First Author | Sun S | Year | 2019 |
| Journal | Genes Dev | Volume | 33 |
| Issue | 15-16 | Pages | 1083-1094 |
| PubMed ID | 31296559 | Mgi Jnum | J:284181 |
| Mgi Id | MGI:6390720 | Doi | 10.1101/gad.326868.119 |
| Citation | Sun S, et al. (2019) The orphan nuclear receptor SHP regulates ER stress response by inhibiting XBP1s degradation. Genes Dev 33(15-16):1083-1094 |
| abstractText | 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 polyubiquitination 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. |
