Enhanced Sensitivity to DSS Colitis Caused by a Hypomorphic Mbtps1 Mutation Disrupting the ATF6-driven Unfolded Protein Response

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2009 Feb 10

PMID 19202076

Citations 86

Authors

Katharina Brandl

Sophie Rutschmann

Xiaohong Li

Xin Du

Nengming Xiao

Bernd Schnabl

David A Brenner

Bruce Beutler

Affiliations

Soon will be listed here.

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.

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