The orphan nuclear receptor SHP regulates er stress response by inhibiting XBP1s degradation

Shengyi Sun, Sherwin Kelekar, Steven A Kliewer, David J Mangelsdorf

Research output: Contribution to journalArticle

3 Scopus citations

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 languageEnglish (US)
Pages (from-to)1083-1094
Number of pages12
JournalGenes and Development
Volume33
Issue number15-16
DOIs
StatePublished - Aug 1 2019

Keywords

  • Cullin3
  • ER stress
  • Exocrine pancreas
  • SHP
  • Ubiquitination
  • XBP1s

ASJC Scopus subject areas

  • Genetics
  • Developmental Biology

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