Center for Molecular Biology of Heidelberg University (ZMBH), DKFZ-ZMBH Alliance and CellNetworks Cluster of Excellence, Heidelberg, Germany.
Department of Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Martinsried, Germany.
Elife. 2019 Mar 13;8:e43244. doi: 10.7554/eLife.43244.
Misfolded proteins in the endoplasmic reticulum (ER) activate the unfolded protein response (UPR), which enhances protein folding to restore homeostasis. Additional pathways respond to ER stress, but how they help counteract protein misfolding is incompletely understood. Here, we develop a titratable system for the induction of ER stress in yeast to enable a genetic screen for factors that augment stress resistance independently of the UPR. We identify the proteasome biogenesis regulator Rpn4 and show that it cooperates with the UPR. Rpn4 abundance increases during ER stress, first by a post-transcriptional, then by a transcriptional mechanism. Induction of transcription is triggered by cytosolic mislocalization of secretory proteins, is mediated by multiple signaling pathways and accelerates clearance of misfolded proteins from the cytosol. Thus, Rpn4 and the UPR are complementary elements of a modular cross-compartment response to ER stress.
内质网（ER）中错误折叠的蛋白质会激活未折叠蛋白反应（UPR），从而增强蛋白质折叠以恢复内稳态。其他途径也会对 ER 应激做出反应，但它们如何帮助对抗蛋白质错误折叠的机制尚不完全清楚。在这里，我们开发了一种可滴定的酵母 ER 应激诱导系统，以实现遗传筛选，寻找独立于 UPR 增强应激抗性的因素。我们鉴定了蛋白酶体生物发生调节剂 Rpn4，并表明它与 UPR 合作。在 ER 应激期间，Rpn4 的丰度首先通过转录后机制增加，然后通过转录机制增加。转录的诱导是由分泌蛋白的细胞质定位错误引发的，由多种信号通路介导，并加速了错误折叠蛋白从细胞质中的清除。因此，Rpn4 和 UPR 是内质网应激模块化细胞间反应的互补元素。
