期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2014
卷号：111
期号：41
页码：14800-14805
DOI：10.1073/pnas.1409588111
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceThe unfolded protein response (UPR) maintains protein-folding homeostasis in the endoplasmic reticulum (ER). The UPR is involved in diseases such as triple-negative breast cancer, developmental processes such as B-cell activation, and the decision to commit to apoptosis. In principle, the UPR could restore homeostasis to the ER by increasing folding capacity or reducing the load of newly synthesized proteins. Here we report that budding yeast augments the UPR with PKA signaling and reduces the load of newly synthesized proteins, a role functionally analogous to the PKR-like ER kinase (PERK) and regulated inositol-requiring enzyme 1 (IRE1)-dependent mRNA decay (RIDD) pathways in other organisms. Accounting for all the pathways that contribute to stress resistance is necessary to understand how perturbations, including targeted therapies, propagate through the cell. During environmental, developmental, or genetic stress, the cell's folding capacity can become overwhelmed, and misfolded proteins can accumulate in all cell compartments. Eukaryotes evolved the unfolded protein response (UPR) to counteract proteotoxic stress in the endoplasmic reticulum (ER). Although the UPR is vital to restoring homeostasis to protein folding in the ER, it has become evident that the response to ER stress is not limited to the UPR. Here, we used engineered orthogonal UPR induction, deep mRNA sequencing, and dynamic flow cytometry to dissect the cell's response to ER stress comprehensively. We show that budding yeast augments the UPR with time-delayed Ras/PKA signaling. This second wave of transcriptional dynamics is independent of the UPR and is necessary for fitness in the presence of ER stress, partially due to a reduction in general protein synthesis. This Ras/PKA-mediated effect functionally mimics other mechanisms, such as translational control by PKR-like ER kinase (PERK) and regulated inositol-requiring enzyme 1 (IRE1)-dependent mRNA decay (RIDD), which reduce the load of proteins entering the ER in response to ER stress in metazoan cells.
