The evolving role of ubiquitin modification in endoplasmic reticulum-associated degradation.
The evolving role of ubiquitin modification in endoplasmic reticulum-associated degradation.
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DOI：
10.1042/bcj20160582
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发表时间：
2017-02-15
期刊：
影响因子：
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通讯作者：
Brodsky JL
中科院分区：
文献类型：
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作者：
Preston GM;Brodsky JL
内质网（ER）作为一个仓库，增加和控制进入分泌途径的新生蛋白质的生物发生。反过来，这个隔室也包含了对错误折叠蛋白质的反应机制，通过一个被称为er相关降解（ERAD）的过程来靶向蛋白质水解。在ERAD期间，底物被选择，用泛素修饰，从内质网中去除，然后由细胞质26S蛋白酶体降解。虽然整体膜蛋白可以直接进入位于细胞质或内质膜表面的泛素化机制，但管腔内的可溶性ERAD底物必须从这个隔室逆行转运。无论哪种情况，几乎所有ERAD底物都带有多泛素链标记，这种修饰代表了降解异常蛋白的承诺步骤。然而，越来越多的证据表明，ERAD底物上的多泛素链可以被进一步修饰，用于募集ERAD所需因子，并可能调节ERAD机制。ERAD底物上除赖氨酸外的氨基酸侧链也可以被泛素修饰，并且已经观察到影响底物泛素化的翻译后修饰。在这里，我们总结了这些数据，并概述了推动这一研究领域的问题。
The endoplasmic reticulum (ER) serves as a warehouse for factors that augment and control the biogenesis of nascent proteins entering the secretory pathway. In turn, this compartment also harbors the machinery that responds to the presence of misfolded proteins by targeting them for proteolysis via a process known as ER-associated degradation (ERAD). During ERAD, substrates are selected, modified with ubiquitin, removed from the ER, and then degraded by the cytoplasmic 26S proteasome. While integral membrane proteins can directly access the ubiquitination machinery that resides in the cytoplasm or on the cytoplasmic face of the ER membrane, soluble ERAD substrates within the lumen must be retrotranslocated from this compartment. In either case, nearly all ERAD substrates are tagged with a polyubiquitin chain, a modification that represents a commitment step to degrade aberrant proteins. However, increasing evidence indicates that the polyubiquitin chain on ERAD substrates can be further modified, serves to recruit ERAD-requiring factors, and may regulate the ERAD machinery. Amino acid side chains other than lysine on ERAD substrates can also be modified with ubiquitin, and post-translational modifications that affect substrate ubiquitination have been observed. Here, we summarize these data and provide an overview of questions driving this field of research.