Enhanced sensitivity to DSS colitis caused by a hypomorphic Mbtps1 mutation disrupting the ATF6-driven unfolded protein response

Katharina Brandl, Sophie Rutschmann, Xiaohong Li, Xin Du, Nengming Xiao, Bernd Schnabl, David A. Brenner, Bruce Beutler

Research output: Contribution to journalArticle

97 Scopus citations

Abstract

Here, we describe an N-ethyl-N-nitrosourea (ENU)-induced missense error in the membrane-bound transcription factor peptidase site 1 (S1P)-encoding gene (Mbtps1) that causes enhanced susceptibility to dextran sodium sulfate (DSS)-induced colitis. S1P cleaves and activates cAMP response element binding protein/ATF transcription factors, the sterol regulatory element-binding proteins (SREBPs), and other proteins of both endogenous and viral origin. Because S1P has a nonredundant function in the ATF6-dependent unfolded protein response (UPR), woodrat mice show diminished levels of major endoplasmic reticulum chaperones GRP78 (BiP) and GRP94 in the colon upon DSS administration. Experiments with bone marrow chimeric mice reveal a requirement for S1P in nonhematopoietic cells, without which a diminished UPR and colitis develop.

Original languageEnglish (US)
Pages (from-to)3300-3305
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume106
Issue number9
DOIs
StatePublished - Mar 3 2009

Keywords

  • ER stress
  • Inflammatory bowel disease
  • Site 1 protease
  • UPR

ASJC Scopus subject areas

  • General

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