Ufd2p synthesizes branched ubiquitin chains to promote the degradation of substrates modified with atypical chains.
Ufd2p synthesizes branched ubiquitin chains to promote the degradation of substrates modified with atypical chains.
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Ufd2p合成支化泛素链促进非典型链修饰底物的降解
DOI：
10.1038/ncomms14274
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发表时间：
2017-02-06
影响因子：
16.6
通讯作者：
Li W
中科院分区：
文献类型：
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作者：
Liu C;Liu W;Ye Y;Li W
由泛素链延伸因子（E4）（酿酒酵母中以Ufd2p为代表）对部分蛋白质进行的泛素化修饰，是许多生物学过程的关键调节机制。然而，Ufd2p介导的泛素化修饰机制在很大程度上仍不明确。在此，我们发现Ufd2p可催化由泛素连接酶（Ufd4p）组装的K29连接的泛素链上发生K48连接的多单泛素化，从而形成分支状泛素链。该反应依赖于K29连接的泛素链与Ufd2p的两个N端环的相互作用。只有在K29连接的泛素链修饰的底物上添加K48连接的泛素后，底物才能被转运至蛋白酶体进行降解。我们证明，这种泛素链连接方式的转换反应对于酵母的内质网相关蛋白降解（ERAD）、油酸抗性和耐酸性至关重要。因此，我们的研究结果表明，Ufd2p通过转换泛素链连接方式发挥作用，使那些通常不会被靶向蛋白酶体的、以某种泛素连接方式修饰的蛋白质得以降解。
泛素化对其修饰的蛋白质的影响因泛素部分之间连接方式的不同而有所差异。在此，刘等人展示了酵母Udf2p如何促进在K29连接的链上形成K48连接，从而生成将其底物靶向蛋白酶体的分支状K29 - K48泛素链。
Ubiquitination of a subset of proteins by ubiquitin chain elongation factors (E4), represented by Ufd2p inSaccharomyces cerevisiae, is a pivotal regulator for many biological processes. However, the mechanism of Ufd2p-mediated ubiquitination is largely unclear. Here, we show that Ufd2p catalyses K48-linked multi-monoubiquitination on K29-linked ubiquitin chains assembled by the ubiquitin ligase (Ufd4p), resulting in branched ubiquitin chains. This reaction depends on the interaction of K29-linked ubiquitin chains with two N-terminal loops of Ufd2p. Only following the addition of K48-linked ubiquitin to substrates modified with K29-linked ubiquitin chains, can the substrates be escorted to the proteasome for degradation. We demonstrate that this ubiquitin chain linkage switching reaction is essential for ERAD, oleic acid and acid pH resistance in yeast. Thus, our results suggest that Ufd2p functions by switching ubiquitin chain linkages to allow the degradation of proteins modified with a ubiquitin linkage, which is normally not targeted to the proteasome.