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

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

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Orphan Nuclear Receptors
Endoplasmic Reticulum Stress
Proteolysis
Ceruletide
Co-Repressor Proteins
Exocrine Pancreas
Ubiquitin-Protein Ligases
Acinar Cells
Protein Stability
Heat-Shock Proteins
Bile Acids and Salts
Lipid Metabolism
Endoplasmic Reticulum
Pancreatitis
Transcriptional Activation
Proteins
Homeostasis
X-Box Binding Protein 1
Liver

Keywords

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

ASJC Scopus subject areas

  • Genetics
  • Developmental Biology

Cite this

The orphan nuclear receptor SHP regulates er stress response by inhibiting XBP1s degradation. / Sun, Shengyi; Kelekar, Sherwin; Kliewer, Steven A; Mangelsdorf, David J.

In: Genes and Development, Vol. 33, No. 15-16, 01.08.2019, p. 1083-1094.

Research output: Contribution to journalArticle

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