INSIG: a broadly conserved transmembrane chaperone for sterol-sensing domain proteins
INSIG: a broadly conserved transmembrane chaperone for sterol-sensing domain proteins
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DOI：
10.1038/sj.emboj.7600855
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发表时间：
2005-11-16
期刊：
影响因子：
11.4
通讯作者：
Hampton, RY
中科院分区：
文献类型：
--
作者：
Flury, I;Garza, R;Hampton, RY
INSIGs是哺乳动物蛋白SCAP(SREBP裂解激活蛋白)和HMG-CoA还原酶(HMGR)的基础蛋白，是固醇调节的基础蛋白。INSIG在调节这些效应器方面执行不同的任务：它们促进SCAP的内质网滞留，但泛素介导的HMGR降解。从INSIG的发现和研究中产生的两个问题是：它们如何执行这些不同的任务，以及INSIG在生物学中的行为有多普遍？我们现在证明了酵母INSIG同源物NSG1和NSG2的功能控制酵母Hmg2p的稳定性，HMGR同工酶经历调节的泛素化。酵母Nsgs通过直接与含有甾醇敏感结构域(SSD)的跨膜区相互作用，以高度特异的方式抑制Hmg2p的降解。当两种蛋白质都处于天然水平时，Nsg1p自然起到限制Hmg2p降解的作用，这表明这两类蛋白质之间存在长期的功能相互作用。一种统一已知的、不同的INSIG作用的方法是将它们视为专门针对含有SSD的客户蛋白的伴侣的已知改编。
INSIGs are proteins that underlie sterol regulation of the mammalian proteins SCAP (SREBP cleavage activating protein) and HMG-CoA reductase (HMGR). The INSIGs perform distinct tasks in the regulation of these effectors: they promote ER retention of SCAP, but ubiquitin-mediated degradation of HMGR. Two questions that arise from the discovery and study of INSIGs are: how do they perform these distinct tasks, and how general are the actions of INSIGs in biology? We now show that the yeast INSIG homologs NSG1 and NSG2 function to control the stability of yeast Hmg2p, the HMGR isozyme that undergoes regulated ubiquitination. Yeast Nsgs inhibit degradation of Hmg2p in a highly specific manner, by directly interacting with the sterol-sensing domain (SSD)-containing transmembrane region. Nsg1p functions naturally to limit degradation of Hmg2p when both proteins are at native levels, indicating a long-standing functional interplay between these two classes of proteins. One way to unify the known, disparate actions of INSIGs is to view them as known adaptations of a chaperone dedicated to SSD-containing client proteins.