Previously unknown role for the ubiquitin ligase Ubr1 in endoplasmic reticulum-associated protein degradation
Previously unknown role for the ubiquitin ligase Ubr1 in endoplasmic reticulum-associated protein degradation
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DOI：
10.1073/pnas.1304928110
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发表时间：
2013-08
期刊：
影响因子：
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通讯作者：
Alexandra Stolz;Stefanie Besser;Heike Hottmann;D. Wolf
中科院分区：
文献类型：
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作者：
Alexandra Stolz;Stefanie Besser;Heike Hottmann;D. Wolf
意义-这项研究描述了一个以前未知的作用，胞质泛素连接酶Ubr 1在内质网相关的蛋白质降解，从而连接蛋白质的内质网和胞质溶胶的质量控制过程。质量控制和错误折叠蛋白质的降解是所有细胞的基本过程。内质网（ER）是蛋白质进入分泌途径的入口位点，其中蛋白质折叠发生，并且末端错误折叠的蛋白质被识别并逆转运穿过ER膜进入胞质溶胶。在此，蛋白质通过酵母中的Hrd 1/Der 3（HMG-CoA还原酶降解/ER降解）和Doa 10（α降解）中的膜包埋的泛素连接酶之一进行多聚泛素化，并被蛋白酶体降解。在这项研究中，我们确定胞质Ubr 1（E3泛素连接酶，N-识别）作为一个额外的泛素连接酶，可以参与ER相关蛋白降解（ERAD）在酵母中。我们发现，两个多位ERAD基板，突变的转运交配型信息素，Ste 6 *（无菌），囊性纤维化跨膜传导调节器，在典型的ER泛素连接酶的存在和不存在下进行Ubr 1依赖性降解。然而，在Ste 6 * Ubr 1的情况下，在应激条件如热或乙醇下或在不存在典型ER连接酶的情况下是特别需要的，人囊性纤维化跨膜传导调节因子的有效降解需要在标准生长条件下野生型细胞中已经存在的Ubr 1的功能。与热休克蛋白70（热休克蛋白）伴侣蛋白Ssa 1（应激-七十亚家族A）和AAA型ATP酶Cdc 48（细胞分裂周期）一起，Ubr 1指导底物进行蛋白酶体降解。这些数据揭示了ERAD的另一层复杂性。
Significance The study describes a previously unknown role for the cytosolic ubiquitin ligase Ubr1 in endoplasmic reticulum-associated protein degradation, thereby connecting the protein quality control processes of the endoplasmic reticulum and of the cytosol. Quality control and degradation of misfolded proteins are essential processes of all cells. The endoplasmic reticulum (ER) is the entry site of proteins into the secretory pathway in which protein folding occurs and terminally misfolded proteins are recognized and retrotranslocated across the ER membrane into the cytosol. Here, proteins undergo polyubiquitination by one of the membrane-embedded ubiquitin ligases, in yeast Hrd1/Der3 (HMG-CoA reductase degradation/degradation of the ER) and Doa10 (degradation of alpha), and are degraded by the proteasome. In this study, we identify cytosolic Ubr1 (E3 ubiquitin ligase, N-recognin) as an additional ubiquitin ligase that can participate in ER-associated protein degradation (ERAD) in yeast. We show that two polytopic ERAD substrates, mutated transporter of the mating type a pheromone, Ste6* (sterile), and cystic fibrosis transmembrane conductance regulator, undergo Ubr1-dependent degradation in the presence and absence of the canonical ER ubiquitin ligases. Whereas in the case of Ste6* Ubr1 is specifically required under stress conditions such as heat or ethanol or in the absence of the canonical ER ligases, efficient degradation of human cystic fibrosis transmembrane conductance regulator requires function of Ubr1 already in wild-type cells under standard growth conditions. Together with the Hsp70 (heat shock protein) chaperone Ssa1 (stress-seventy subfamily A) and the AAA-type ATPase Cdc48 (cell division cycle), Ubr1 directs the substrate to proteasomal degradation. These data unravel another layer of complexity in ERAD.