Center for Molecular Biology of Heidelberg University (ZMBH), DKFZ-ZMBH Alliance and CellNetworks Cluster of Excellence, 69120 Heidelberg, Germany.
Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA 94143, USA.
Mol Cell. 2018 Jun 21;70(6):1025-1037.e5. doi: 10.1016/j.molcel.2018.04.027. Epub 2018 May 31.
When faced with proteotoxic stress, cells mount adaptive responses to eliminate aberrant proteins. Adaptive responses increase the expression of protein folding and degradation factors to enhance the cellular quality control machinery. However, it is unclear whether and how this augmented machinery acquires new activities during stress. Here, we uncover a regulatory cascade in budding yeast that consists of the hydrophilin protein Roq1/Yjl144w, the HtrA-type protease Ynm3/Nma111, and the ubiquitin ligase Ubr1. Various stresses stimulate ROQ1 transcription. The Roq1 protein is cleaved by Ynm3. Cleaved Roq1 interacts with Ubr1, transforming its substrate specificity. Altered substrate recognition by Ubr1 accelerates proteasomal degradation of misfolded as well as native proteins at the endoplasmic reticulum membrane and in the cytosol. We term this pathway stress-induced homeostatically regulated protein degradation (SHRED) and propose that it promotes physiological adaptation by reprogramming a key component of the quality control machinery.
当细胞面临蛋白毒性应激时，会启动适应性反应以消除异常蛋白。适应性反应会增加蛋白折叠和降解因子的表达，以增强细胞的质量控制机制。然而，目前尚不清楚这个增强的机制在应激过程中是否以及如何获得新的活性。在这里，我们在 budding yeast 中发现了一个由亲水性蛋白 Roq1/Yjl144w、HtrA 型蛋白酶 Ynm3/Nma111 和泛素连接酶 Ubr1 组成的调控级联。各种应激刺激 ROQ1 的转录。Roq1 蛋白被 Ynm3 切割。切割后的 Roq1 与 Ubr1 相互作用，改变其底物特异性。Ubr1 改变的底物识别加速了内质网膜和细胞质中错误折叠和天然蛋白的蛋白酶体降解。我们将此途径称为应激诱导的稳态调节蛋白降解 (SHRED)，并提出它通过重新编程质量控制机制的关键组成部分来促进生理适应。
