Enhanced sensitivity to DSS colitis caused by a hypomorphic Mbtps1 mutation disrupting the ATF6-driven unfolded protein response
Enhanced sensitivity to DSS colitis caused by a hypomorphic Mbtps1 mutation disrupting the ATF6-driven unfolded protein response
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DOI：
10.1073/pnas.0813036106
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发表时间：
2009-03-03
影响因子：
11.1
通讯作者：
Beutler, Bruce
中科院分区：
文献类型：
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作者：
Brandl, Katharina;Rutschmann, Sophie;Beutler, Bruce
在这里，我们描述了膜结合的转录因子肽酶位点1（S1P） - 编码基因（MBTPS1）中的N-乙基N-氮（ENU）诱导的错义误差，从而引起对硫酸葡萄糖硫酸钠（DSS） - DSS） - 诱发结肠炎。 S1P切割并激活CAMP响应元件结合蛋白/ATF转录因子，固醇调节元素结合蛋白（SREBPS）以及内源性和病毒起源的其他蛋白质。由于S1P在ATF6依赖性展开的蛋白质反应（UPR）中具有非冗余功能，因此伍德拉特小鼠在DSS给药时在结肠中显示出主要的内质网伴侣GRP78（BIP）和GRP94的水平降低。对骨髓嵌合小鼠进行的实验揭示了非杂造细胞中S1P的需求，否则，UPR和结肠炎会降低。
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.