title: Delayed Ras/PKA signaling augments the unfolded protein response.
abstract: 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.
authors.affiliation: Department of Biochemistry and Biophysics, California Institute for Quantitative Biosciences, and.
authors.forename: David
authors.initials: D
authors.lastname: Pincus
authors.affiliation: Department of Biochemistry and Biophysics, California Institute for Quantitative Biosciences, and.
authors.forename: Andrés
authors.initials: A
authors.lastname: Aranda-Díaz
authors.affiliation: Department of Biochemistry and Biophysics, California Institute for Quantitative Biosciences, and.
authors.forename: Ignacio A
authors.identifier: http://orcid.org/0000-0002-1113-7083
authors.initials: IA
authors.lastname: Zuleta
authors.affiliation: Department of Biochemistry and Biophysics, California Institute for Quantitative Biosciences, and Howard Hughes Medical Institute, University of California, San Francisco, CA 94158 peter@walterlab.ucsf.edu hana.el-samad@ucsf.edu.
authors.forename: Peter
authors.initials: P
authors.lastname: Walter
authors.affiliation: Department of Biochemistry and Biophysics, California Institute for Quantitative Biosciences, and peter@walterlab.ucsf.edu hana.el-samad@ucsf.edu.
authors.forename: Hana
authors.initials: H
authors.lastname: El-Samad
mesh_terms: D050976:Basic-Leucine Zipper Transcription Factors / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects / Q000235:genetics; D004789:Enzyme Activation / Q000187:drug effects; D014176:Protein Biosynthesis / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D012097:Repressor Proteins / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D014158:Transcription, Genetic / Q000187:drug effects; D014415:Tunicamycin / Q000494:pharmacology; D056811:Unfolded Protein Response / Q000187:drug effects / Q000235:genetics; D018631:ras Proteins / Q000378:metabolism*
chemical_list: D050976:Basic-Leucine Zipper Transcription Factors; C091341:HAC1 protein, S cerevisiae; D047428:Protein Kinase Inhibitors; D012097:Repressor Proteins; D029701:Saccharomyces cerevisiae Proteins; D014415:Tunicamycin; D017868:Cyclic AMP-Dependent Protein Kinases; D018631:ras Proteins