由低表达的Mbtps1突变破坏ATF6驱动的未折叠蛋白反应所导致的对葡聚糖硫酸钠（DSS）结肠炎的敏感性增强。
Enhanced sensitivity to DSS colitis caused by a hypomorphic Mbtps1 mutation disrupting the ATF6-driven unfolded protein response.
作者信息
Brandl Katharina, Rutschmann Sophie, Li Xiaohong, Du Xin, Xiao Nengming, Schnabl Bernd, Brenner David A, Beutler Bruce
机构信息
Department of Genetics, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
出版信息
Proc Natl Acad Sci U S A. 2009 Mar 3;106(9):3300-5. doi: 10.1073/pnas.0813036106. Epub 2009 Feb 6.
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.
摘要
在此，我们描述了一种由N-乙基-N-亚硝基脲（ENU）诱导的错义突变，该突变发生在膜结合转录因子肽酶位点1（S1P）编码基因（Mbtps1）中，导致对葡聚糖硫酸钠（DSS）诱导的结肠炎易感性增强。S1P可切割并激活环磷酸腺苷反应元件结合蛋白/活化转录因子（ATF）转录因子、固醇调节元件结合蛋白（SREBP）以及其他内源性和病毒源性蛋白。由于S1P在ATF6依赖的未折叠蛋白反应（UPR）中具有不可替代的功能，在给予DSS后，林鼠结肠中主要内质网伴侣蛋白GRP78（BiP）和GRP94的水平降低。对骨髓嵌合小鼠的实验表明，非造血细胞中需要S1P，否则会出现UPR减弱和结肠炎。
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