Schäfer Antje, Wolf Dieter H
Institute of Biochemistry, University of Stuttgart, Stuttgart, Germany.
EMBO J. 2009 Oct 7;28(19):2874-84. doi: 10.1038/emboj.2009.231. Epub 2009 Aug 20.
Endoplasmic reticulum-associated degradation (ERAD) is a cellular pathway for the disposal of misfolded secretory proteins. This process comprises recognition of the misfolded proteins followed by their retro-translocation across the ER membrane into the cytosol in which polyubiquitination and proteasomal degradation occur. A variety of data imply that the protein import channel Sec61p has a function in the ERAD process. Until now, no physical interactions between Sec61p and other essential components of the ERAD pathway could be found. Here, we establish this link by showing that Hrd3p, which is part of the Hrd-Der ubiquitin ligase complex, and other core components of the ERAD machinery physically interact with Sec61p. In addition, we study binding of misfolded CPY(*) proteins to Sec61p during the process of degradation. We show that interaction with Sec61p is maintained until the misfolded proteins are ubiquitinated on the cytosolic side of the ER. Our observations suggest that Sec61p contacts an ERAD ligase complex for further elimination of ER lumenal misfolded proteins.
内质网相关降解（ERAD）是一种处理错误折叠的分泌蛋白的细胞途径。该过程包括识别错误折叠的蛋白质，随后将其通过内质网膜逆向转运到胞质溶胶中，在胞质溶胶中发生多聚泛素化和蛋白酶体降解。各种数据表明，蛋白质导入通道Sec61p在ERAD过程中发挥作用。到目前为止，尚未发现Sec61p与ERAD途径的其他必需成分之间存在物理相互作用。在此，我们通过证明作为Hrd-Der泛素连接酶复合体一部分的Hrd3p以及ERAD机制的其他核心成分与Sec61p存在物理相互作用，建立了这种联系。此外，我们研究了错误折叠的CPY（*）蛋白在降解过程中与Sec61p的结合。我们表明，与Sec61p的相互作用一直维持到错误折叠的蛋白质在内质网胞质侧被泛素化。我们的观察结果表明，Sec61p与一种ERAD连接酶复合体接触，以进一步清除内质网腔中错误折叠的蛋白质。
