Role of 26S proteasome and HRD genes in the degradation of 3-hydroxy-3-methylglutaryl-CoA reductase, an integral endoplasmic reticulum membrane protein
Role of 26S proteasome and HRD genes in the degradation of 3-hydroxy-3-methylglutaryl-CoA reductase, an integral endoplasmic reticulum membrane protein
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DOI：
10.1091/mbc.7.12.2029
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发表时间：
1996-12-01
影响因子：
3.3
通讯作者：
Rine, J
中科院分区：
文献类型：
--
作者：
Hampton, RY;Gardner, RG;Rine, J
3-羟基-3-甲基戊二酰辅酶a还原酶（HMG-R）是内质网（ER）不可或缺的膜蛋白，是甾醇合成的关键酶。在人类和酵母中，HMG-R在内质网或内质网中被降解。HMG-R的降解作为甲羟戊酸途径反馈控制的一部分受到调节。降解的机制和将HMG-R降解与甲羟戊酸途径相结合的信号的性质都不清楚。我们对酿酒酵母中HMG-R的降解进行了遗传分析，选择了缺乏HMG-R同工酶Hmg2p降解的突变体。潜在的基因被称为HRD（发音为“herd”），用于HMG-CoA还原酶降解。到目前为止，我们已经发现了三个基因的突变：HRD1， HRD2和HRD3。HRD2基因序列与26S蛋白酶体的p97激活子同源。这种p97蛋白，也被称为TRAP-2，被认为是成熟的26S蛋白酶体的一个组成部分。hrd2-1突变体在蛋白酶体受损的细胞中具有许多多效性表型，这些表型由人类TRAP-2/p97编码区补充。相比之下，HRD1和HRD3基因编码了先前未知的膜结合蛋白。Hrd3p蛋白与秀丽隐杆线虫se1-1蛋白同源，se1-1蛋白是至少两种不同膜蛋白的负调节因子，并且含有与其他几种蛋白共享的HRD3基序。Hrd1p没有全长同源物，但含有H2环指基序。这些数据提示了内质网蛋白降解模型，其中Hrd1p和Hrd3p蛋白共同将HMG-R传递到26S蛋白酶体。此外，我们的研究结果在体内支持了p97/TRAP-2/Hrd2p蛋白作为26S蛋白酶体的重要功能成分的作用。因为HRD基因是内质网降解的调节底物和不调节底物的降解所必需的，所以HRD基因是HMG-R降解的媒介，而不是这种降解的调节者。
3-hydroxy-3-methylglutaryl-CoA reductase (HMG-R), a key enzyme of sterol synthesis, is an integral membrane protein of the endoplasmic reticulum (ER). In both humans and yeast, HMG-R is degraded at or in the ER. The degradation of HMG-R is regulated as part of feedback control of the mevalonate pathway. Neither the mechanism of degradation nor the nature of the signals that couple the degradation of HMG-R to the mevalonate pathway: is known. We have launched a genetic analysis of the degradation of HMG-R in Saccharomyces cerevisiae using a selection for mutants that are deficient in the degradation of Hmg2p, an HMG-R isozyme. The underlying genes are called HRD (pronounced ''herd''), for HMG-CoA reductase degradation. So far we have discovered mutants in three genes: HRD1, HRD2, and HRD3. The sequence of the HRD2 gene is homologous to the p97 activator of the 26S proteasome. This p97 protein, also called TRAP-2 has been proposed to be a component of the mature 26S proteasome. The hrd2-1 mutant had numerous pleiotropic phenotypes expected for cells with a compromised proteasome, and these phenotypes were complemented by the human TRAP-2/p97 coding region. In contrast, HRD1 and HRD3 genes encoded previously unknown proteins predicted to be membrane bound. The Hrd3p protein was homologous to the Caenorhabditis elegans se1-1 protein, a negative regulator of at least two different membrane proteins, and contained an HRD3 motif shared with several other proteins. Hrd1p had no full-length homologues, but contained an H2 ring finger motif. These data suggested a model of ER protein degradation in which the Hrd1p and Hrd3p proteins conspire to deliver HMG-R to the 26S proteasome. Moreover, our results lend in vivo support to the proposed role of the p97/TRAP-2/Hrd2p protein as a functionally important component of the 26S proteasome. Because the HRD genes were required for the degradation of both regulated and unregulated substrates of ER degradation, the HRD genes are the agents of HMG-R degradation but not the regulators of that degradation.