Ng D T, Spear E D, Walter P
Department of Biochemistry and Molecular Biology, Pennsylvania State University, University Park, Pennsylvania 16802, USA.
J Cell Biol. 2000 Jul 10;150(1):77-88. doi: 10.1083/jcb.150.1.77.
The unfolded protein response (UPR) is an intracellular signaling pathway that relays signals from the lumen of the ER to activate target genes in the nucleus. We devised a genetic screen in the yeast Saccharomyces cerevisiae to isolate mutants that are dependent on activation of the pathway for viability. Using this strategy, we isolated mutants affecting various aspects of ER function, including protein translocation, folding, glycosylation, glycosylphosphatidylinositol modification, and ER-associated protein degradation (ERAD). Extending results gleaned from the genetic studies, we demonstrate that the UPR regulates trafficking of proteins at the translocon to balance the needs of biosynthesis and ERAD. The approach also revealed connections of the UPR to other regulatory pathways. In particular, we identified SON1/RPN4, a recently described transcriptional regulator for genes encoding subunits of the proteasome. Our genetic strategy, therefore, offers a powerful means to provide insight into the physiology of the UPR and to identify novel genes with roles in many aspects of secretory and membrane protein biogenesis.
未折叠蛋白反应（UPR）是一种细胞内信号通路，它将来自内质网腔的信号传递至细胞核以激活靶基因。我们在酿酒酵母中设计了一个遗传筛选实验，以分离那些依赖该通路激活才能存活的突变体。利用这一策略，我们分离出了影响内质网功能各个方面的突变体，包括蛋白质转运、折叠、糖基化、糖基磷脂酰肌醇修饰以及内质网相关蛋白降解（ERAD）。基于从遗传研究中获得的结果进行拓展，我们证明未折叠蛋白反应在转位子处调节蛋白质转运，以平衡生物合成和内质网相关蛋白降解的需求。该方法还揭示了未折叠蛋白反应与其他调控途径的联系。特别是，我们鉴定出了SON1/RPN4，它是最近描述的一种编码蛋白酶体亚基基因的转录调节因子。因此，我们的遗传策略提供了一种强大的手段，有助于深入了解未折叠蛋白反应的生理学，并鉴定在分泌蛋白和膜蛋白生物合成的许多方面发挥作用的新基因。
