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

被引：118

作者：

Brandl, Katharina ^{[1
]}

Rutschmann, Sophie ^{[1
]}

Li, Xiaohong ^{[1
]}

Du, Xin ^{[1
]}

Xiao, Nengming ^{[1
]}

Schnabl, Bernd ^{[2
]}

Brenner, David A. ^{[2
]}

Beutler, Bruce ^{[1
]}

机构：

[1] Scripps Res Inst, Dept Genet, La Jolla, CA 92037 USA

[2] Univ Calif San Diego, Dept Med, La Jolla, CA 92093 USA

来源：

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | 2009年 / 106卷 / 09期

关键词：

ER stress; UPR; site; 1; protease; inflammatory bowel disease; ENDOPLASMIC-RETICULUM STRESS; ER STRESS; TRANSCRIPTION FACTOR; CLEAVAGE; MICE; INFLAMMATION; ATF6; XBP1; PROPROTEIN; ELEMENT;

D O I：

10.1073/pnas.0813036106

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页码：3300 / 3305

页数：6

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