OS-9 facilitates turnover of nonnative GRP94 marked by hyperglycosylation.
OS-9 facilitates turnover of nonnative GRP94 marked by hyperglycosylation.
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DOI：
10.1091/mbc.e14-03-0805
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发表时间：
2014-08-01
影响因子：
3.3
通讯作者：
Argon Y
中科院分区：
文献类型：
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作者：
Dersh D;Jones SM;Eletto D;Christianson JC;Argon Y
ER质量控制因子GRP94和OS-9的结合不是为了处理ERAD底物，而是因为OS-9隔离和降解异常形式的GRP94，GRP94在隐蔽的受体位置高糖基化，并改变结构和活性。这突出了一种新的内质网驻留伴侣的质量控制机制。蛋白质折叠途径与处置机制的紧密耦合促进了内质网(ER)蛋白质生产的效率。有人推测，内质网驻留的分子伴侣葡萄糖调节蛋白94(GRP94)是这种质量控制耦合的一部分，因为它支持特定客户蛋白的折叠，同时也与参与内质网相关降解(ERAD)的凝集素骨肉瘤扩增9(OS-9)紧密结合。为了探索这种可能性，我们研究了GRP94/OS-9复合体在内质网质量控制中的潜在功能。出乎意料的是，GRP94在错误折叠的底物的ERAD中不与OS-9合作，也不直接需要OS-9折叠所需的伴侣。相反，OS-9优先与GRP94的一个亚群结合，该亚群在隐蔽的N-连接的糖链受体位点上高糖基化。高糖基化的GRP94具有非天然构象，活性较低。因此，在OS-9介导的、ERAD不依赖的、溶酶体样机制中，这些物种的降解速度远远快于主要的单糖化形式的GRP94。因此，这项研究阐明了GRP94/OS-9复合体的作用，并描述了一种新的途径，即隐蔽受体位点的糖基化影响内质网驻留伴侣的功能和命运。
ER quality control factors GRP94 and OS-9 associate not for the disposal of ERAD substrates but instead because OS-9 sequesters and degrades aberrant forms of GRP94, which are hyperglycosylated at cryptic acceptor sites and have altered structure and activity. This highlights a novel mechanism of quality control of an ER-resident chaperone. The tight coupling of protein folding pathways with disposal mechanisms promotes the efficacy of protein production in the endoplasmic reticulum (ER). It has been hypothesized that the ER-resident molecular chaperone glucose-regulated protein 94 (GRP94) is part of this quality control coupling because it supports folding of select client proteins yet also robustly associates with the lectin osteosarcoma amplified 9 (OS-9), a component involved in ER-associated degradation (ERAD). To explore this possibility, we investigated potential functions for the GRP94/OS-9 complex in ER quality control. Unexpectedly, GRP94 does not collaborate with OS-9 in ERAD of misfolded substrates, nor is the chaperone required directly for OS-9 folding. Instead, OS-9 binds preferentially to a subpopulation of GRP94 that is hyperglycosylated on cryptic N-linked glycan acceptor sites. Hyperglycosylated GRP94 forms have nonnative conformations and are less active. As a result, these species are degraded much faster than the major, monoglycosylated form of GRP94 in an OS-9–mediated, ERAD-independent, lysosomal-like mechanism. This study therefore clarifies the role of the GRP94/OS-9 complex and describes a novel pathway by which glycosylation of cryptic acceptor sites influences the function and fate of an ER-resident chaperone.