Denic Vladimir, Quan Erin M, Weissman Jonathan S
Howard Hughes Medical Institute, Department of Cellular and Molecular Pharmacology, University of California, San Francisco, CA 94158, USA.
Cell. 2006 Jul 28;126(2):349-59. doi: 10.1016/j.cell.2006.05.045.
How the ER-associated degradation (ERAD) machinery accurately identifies terminally misfolded proteins is poorly understood. For luminal ERAD substrates, this recognition depends on their folding and glycosylation status as well as on the conserved ER lectin Yos9p. Here we show that Yos9p is part of a stable complex that organizes key components of ERAD machinery on both sides of the ER membrane, including the transmembrane ubiquitin ligase Hrd1p. We further demonstrate that Yos9p, together with Kar2p and Hrd3p, forms a luminal surveillance complex that both recruits nonnative proteins to the core ERAD machinery and assists a distinct sugar-dependent step necessary to commit substrates for degradation. When Hrd1p is uncoupled from the Yos9p surveillance complex, degradation can occur independently of the requirement for glycosylation. Thus, Yos9p/Kar2p/Hrd3p acts as a gatekeeper, ensuring correct identification of terminally misfolded proteins by recruiting misfolded forms to the ERAD machinery, contributing to the interrogation of substrate sugar status, and preventing glycosylation-independent degradation.
内质网相关降解（ERAD）机制如何准确识别最终错误折叠的蛋白质，目前还知之甚少。对于内质网腔中的ERAD底物，这种识别取决于它们的折叠和糖基化状态以及保守的内质网凝集素Yos9p。我们在此表明，Yos9p是一个稳定复合物的一部分，该复合物在内质网膜两侧组织ERAD机制的关键组分，包括跨膜泛素连接酶Hrd1p。我们进一步证明，Yos9p与Kar2p和Hrd3p一起形成一个内质网腔监测复合物，该复合物既能将非天然蛋白质招募到核心ERAD机制中，又能协助一个将底物用于降解所需的独特的糖依赖性步骤。当Hrd1p与Yos9p监测复合物解偶联时，降解可以独立于糖基化要求而发生。因此，Yos9p/Kar2p/Hrd3p充当一个把关者，通过将错误折叠形式招募到ERAD机制中确保正确识别最终错误折叠的蛋白质，有助于询问底物的糖状态，并防止非糖基化依赖性降解。
