Human HRD1 promoter carries a functional unfolded protein response element to which XBP1 but not ATF6 directly binds.
Human HRD1 promoter carries a functional unfolded protein response element to which XBP1 but not ATF6 directly binds.
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人HRD1启动子具有功能性展开的蛋白质反应元件，XBP1而非ATF6直接结合。
DOI：
10.1093/jb/mvn091
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发表时间：
2008-10
影响因子：
2.7
通讯作者：
Mori K
中科院分区：
文献类型：
--
作者：
Yamamoto K;Suzuki N;Wada T;Okada T;Yoshida H;Kaufman RJ;Mori K
内质网(ER)中蛋白质的质量控制由两种机制实现，一种是产生性折叠机制，它由一系列内质网定位的分子伴侣和折叠酶(统称为ER伴侣)辅助；另一种是内质网相关降解(ERAD)机制，通过ERAD机制，错误折叠的蛋白质被胞浆中依赖泛素的蛋白酶体系统降解。未折叠蛋白在内质网中的积累激活了未折叠蛋白反应(UPR)，导致内质网伴侣蛋白和ERAD成分的转录诱导。在哺乳动物中，有三条信号通路作用于UPR，即IRE1-XBP1、PERK-ATF4和ATF6通路。对缺乏UPR信号分子的小鼠胚胎成纤维细胞的分析表明，ERAD组分的转录诱导依赖于IRE1-XBP1途径。然而，这一发现的分子基础仍然不清楚。在这里，我们分析了人Hrd1的启动子，它编码ERAD的重要组成部分E3泛素连接酶。我们发现Hrd1的诱导是由两个顺式作用元件介导的，一个是典型的ER应激反应元件，另一个是我们指定为UPR元件II的元件。UPR元件II的存在直接与XBP1结合，而不是ATF6，这至少部分解释了Hrd1诱导对IRE1-XBP1途径的依赖。
Quality control of proteins in the endoplasmic reticulum (ER) is achieved by two mechanisms, the productive folding mechanism, which is assisted by a number of ER-localized molecular chaperones and folding enzymes (collectively termed ER chaperones), and the ER-associated degradation (ERAD) mechanism, by which misfolded proteins are degraded by the ubiquitin-dependent proteasome system in the cytosol. Accumulation of unfolded proteins in the ER activates the unfolded protein response (UPR), resulting in transcriptional induction of ER chaperones and ERAD components. In mammals, three signalling pathways operate for the UPR, namely the IRE1-XBP1, PERK-ATF4 and ATF6 pathways. Analysis of mouse embryonic fibroblasts deficient in UPR signalling molecule indicates that transcriptional induction of ERAD components depends on the IRE1-XBP1 pathway. However, the molecular basis of this finding remains unclear. Here, we analysed the promoter of human HRD1, which encodes an E3 ubiquitin ligase, an important component of ERAD. We found that induction of HRD1 is mediated by two cis-acting elements, a canonical ER stress response element and a novel element we designate as UPR element II. The presence of UPR element II to which XBP1 but not ATF6 directly binds explains at least in part the dependency of HRD1 induction on the IRE1-XBP1 pathway.
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影响因子：
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作者：
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