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未组装的 CD147 是一种内源性内质网相关降解底物。

Unassembled CD147 is an endogenous endoplasmic reticulum-associated degradation substrate.

机构信息

Department of Biology, Stanford University, Stanford, CA 94305, USA.

出版信息

Mol Biol Cell. 2012 Dec;23(24):4668-78. doi: 10.1091/mbc.E12-06-0428. Epub 2012 Oct 24.

DOI:10.1091/mbc.E12-06-0428
PMID:23097496
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC3521676/
Abstract

Degradation of folding- or assembly-defective proteins by the endoplasmic reticulum-associated degradation (ERAD) ubiquitin ligase, Hrd1, is facilitated by a process that involves recognition of demannosylated N-glycans by the lectin OS-9/XTP3-B via the adaptor protein SEL1L. Most of our knowledge of the machinery that commits proteins to this fate in metazoans comes from studies of overexpressed mutant proteins in heterologous cells. In this study, we used mass spectrometry to identify core-glycoslyated CD147 (CD147(CG)) as an endogenous substrate of the ERAD system that accumulates in a complex with OS-9 following SEL1L depletion. CD147 is an obligatory assembly factor for monocarboxylate transporters. The majority of newly synthesized endogenous CD147(CG) was degraded by the proteasome in a Hrd1-dependent manner. CD147(CG) turnover was blocked by kifunensine, and interaction of OS-9 and XTP3-B with CD147(CG) was inhibited by mutations to conserved residues in their lectin domains. These data establish unassembled CD147(CG) as an endogenous, constitutive ERAD substrate of the OS-9/SEL1L/Hrd1 pathway.

摘要

折叠或组装缺陷蛋白的内质网相关降解（ERAD）泛素连接酶 Hrd1 的降解是通过一个过程来促进的，该过程涉及通过衔接蛋白 SEL1L 识别去甘露糖基化 N-糖基化的凝集素 OS-9/XTP3-B。我们对真核生物中使蛋白质具有这种命运的机制的大部分了解来自于在异源细胞中表达过表达的突变蛋白的研究。在这项研究中，我们使用质谱法鉴定核心糖基化的 CD147（CD147(CG)）作为 ERAD 系统的内源性底物，在 SEL1L 耗尽后与 OS-9 积累形成复合物。CD147 是单羧酸转运蛋白的必需组装因子。大多数新合成的内源性 CD147(CG) 以 Hrd1 依赖的方式被蛋白酶体降解。CD147(CG) 周转率被 kifunensine 阻断，并且 OS-9 和 XTP3-B 与 CD147(CG) 的相互作用被其凝集素结构域中保守残基的突变所抑制。这些数据确立了未组装的 CD147(CG) 作为 OS-9/SEL1L/Hrd1 途径的内源性组成型 ERAD 底物。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6bf1/3521676/70ae7c7cbe5b/4668fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6bf1/3521676/6b5c45316a5d/4668fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6bf1/3521676/659f1ba348da/4668fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6bf1/3521676/b16b6217c94d/4668fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6bf1/3521676/70ae7c7cbe5b/4668fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6bf1/3521676/6b5c45316a5d/4668fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6bf1/3521676/659f1ba348da/4668fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6bf1/3521676/b16b6217c94d/4668fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6bf1/3521676/70ae7c7cbe5b/4668fig4.jpg

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Defining human ERAD networks through an integrative mapping strategy.通过整合映射策略定义人类 ERAD 网络。
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