A stalled retrotranslocation complex reveals physical linkage between substrate recognition and proteasomal degradation during ER-associated degradation.
A stalled retrotranslocation complex reveals physical linkage between substrate recognition and proteasomal degradation during ER-associated degradation.
复制标题
停滞的转递转换络合物揭示了在ER相关降解过程中底物识别与蛋白酶体降解之间的物理联系。
DOI：
10.1091/mbc.e12-12-0907
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发表时间：
2013-06
影响因子：
3.3
通讯作者：
Kamura T
中科院分区：
文献类型：
--
作者：
Nakatsukasa K;Brodsky JL;Kamura T
Cdc48p/p97的失活触发了一个复合体的形成，该复合体包含26S蛋白酶体、cdc48p/p97、泛素化底物、Hrd1复合体的部分成分和腔识别因子Yos9p。提出了一个模型，在该模型中，Hrd1复合体将底物识别和降解联系在内质网膜的对侧。在内质网相关降解(ERAD)过程中，内质网中错误折叠的腔蛋白和膜蛋白被跨膜的Hrd1泛素连接酶复合体识别，并被逆转录到胞浆中进行泛素化和降解。虽然人们认为底物只有在ATPase CDC48P/p97作用后才被递送到蛋白酶体，但关于Hrd1复合体如何与CDC48P/p97和蛋白酶体协调底物识别和降解的知识有限。在这里，我们提供了证据表明，CDC48P/p97的失活阻止了逆转位，并触发了包含26S蛋白酶体、CDC48P/p97、泛素化底物、Hrd1复合体的部分成分和腔识别因子Yos9p的复合体的形成。我们认为，在ERAD过程中，CDC48P/p97和蛋白酶体的作用是紧密耦合的。我们的数据也支持一个模型，在该模型中，Hrd1复合体将底物识别和内质网膜相反侧的降解联系起来。
Inactivation of Cdc48p/p97 triggers formation of a complex that contains the 26S proteasome, Cdc48p/p97, ubiquitinated substrates, select components of the Hrd1 complex, and the lumenal recognition factor, Yos9p. A model is proposed in which the Hrd1 complex links substrate recognition and degradation on opposite sides of the ER membrane. During endoplasmic reticulum–associated degradation (ERAD), misfolded lumenal and membrane proteins in the ER are recognized by the transmembrane Hrd1 ubiquitin ligase complex and retrotranslocated to the cytosol for ubiquitination and degradation. Although substrates are believed to be delivered to the proteasome only after the ATPase Cdc48p/p97 acts, there is limited knowledge about how the Hrd1 complex coordinates with Cdc48p/p97 and the proteasome to orchestrate substrate recognition and degradation. Here we provide evidence that inactivation of Cdc48p/p97 stalls retrotranslocation and triggers formation of a complex that contains the 26S proteasome, Cdc48p/p97, ubiquitinated substrates, select components of the Hrd1 complex, and the lumenal recognition factor, Yos9p. We propose that the actions of Cdc48p/p97 and the proteasome are tightly coupled during ERAD. Our data also support a model in which the Hrd1 complex links substrate recognition and degradation on opposite sides of the ER membrane.