title: IRE1- and HAC1-independent transcriptional regulation in the unfolded protein response of yeast.
abstract: The unfolded protein response (UPR) is a signalling pathway leading to transcriptional activation of genes that protect cells from accumulation of unfolded proteins in the lumen of the endoplasmic reticulum (ER). In yeast, the only known ER stress signalling pathway originates at the type I transmembrane protein kinase/endoribonuclease Ire1p. Ire1p regulates synthesis of the basic leucine-zipper (bZIP)-containing transcription factor Hac1p by controlling splicing of HAC1 mRNA. Only spliced HAC1 mRNA (HAC1i) is translated, and Hac1ip activates transcription of genes that contain a conserved UPR element (UPRE) in their promoters. Here, we demonstrate that in addition to this well-understood ER stress signalling pathway, a second, IRE1, HAC1 and UPRE-independent mechanism for transcriptional activation upon ER stress, exists in yeast. A genetic screen identified recessive SIN4 alleles as suppressors of a defective UPR in ire1 Delta strains. Elevation of basal transcription in sin4 strains or by tethering the RNA polymerase II holoenzyme with LexAp-holoenzyme component fusion proteins to a promoter allowed for activation of the promoter by ER stress in an IRE1, HAC1 and UPRE-independent manner. We propose that this novel second ER-to-nucleus signal transduction pathway culminates in core promoter activation (CPA) through stimulation of RNA polymerase II holoenzyme activity. Core promoter activation was observed upon diverse cellular stresses, suggesting it represents a primordial stress-induced gene activation mechanism.
authors.affiliation: Howard Hughes Medical Institute, University of Michigan Medical Center, Ann Arbor, MI, USA.
authors.forename: Martin
authors.initials: M
authors.lastname: Schröder
authors.forename: Robert
authors.initials: R
authors.lastname: Clark
authors.forename: Randal J
authors.initials: RJ
authors.lastname: Kaufman
mesh_terms: D000483:Alleles; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism; D050976:Basic-Leucine Zipper Transcription Factors; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D015966:Gene Expression Regulation, Fungal; D056892:Mediator Complex; D008562:Membrane Glycoproteins / Q000502:physiology; D011401:Promoter Regions, Genetic / Q000235:genetics; D017510:Protein Folding; D017346:Protein Serine-Threonine Kinases / Q000502:physiology; D012319:RNA Polymerase II / Q000235:genetics / Q000378:metabolism; D012326:RNA Splicing; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D012097:Repressor Proteins / Q000502:physiology; D012441:Saccharomyces cerevisiae / Q000235:genetics*; D029701:Saccharomyces cerevisiae Proteins / Q000096:biosynthesis / Q000235:genetics* / Q000502:physiology*; D012697:Serine Endopeptidases / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D015534:Trans-Activators / Q000235:genetics / Q000502:physiology*; D014157:Transcription Factors / Q000502:physiology; D014158:Transcription, Genetic / Q000502:physiology*; D015533:Transcriptional Activation; D000099160:LexA Repressor Protein
chemical_list: D001426:Bacterial Proteins; D050976:Basic-Leucine Zipper Transcription Factors; D056892:Mediator Complex; D008562:Membrane Glycoproteins; D017346:Protein Serine-Threonine Kinases; D012319:RNA Polymerase II; D011993:Recombinant Fusion Proteins; D012097:Repressor Proteins; D029701:Saccharomyces cerevisiae Proteins; D012697:Serine Endopeptidases; D015534:Trans-Activators; D014157:Transcription Factors; D000099160:LexA Repressor Protein; C091341:HAC1 protein, S cerevisiae; C076878:SIN4 protein, S cerevisiae; C082863:IRE1 protein, S cerevisiae