title: Messenger RNA targeting to endoplasmic reticulum stress signalling sites.
abstract: Deficiencies in the protein-folding capacity of the endoplasmic reticulum (ER) in all eukaryotic cells lead to ER stress and trigger the unfolded protein response (UPR). ER stress is sensed by Ire1, a transmembrane kinase/endoribonuclease, which initiates the non-conventional splicing of the messenger RNA encoding a key transcription activator, Hac1 in yeast or XBP1 in metazoans. In the absence of ER stress, ribosomes are stalled on unspliced HAC1 mRNA. The translational control is imposed by a base-pairing interaction between the HAC1 intron and the HAC1 5' untranslated region. After excision of the intron, transfer RNA ligase joins the severed exons, lifting the translational block and allowing synthesis of Hac1 from the spliced HAC1 mRNA to ensue. Hac1 in turn drives the UPR gene expression program comprising 7-8% of the yeast genome to counteract ER stress. Here we show that, on activation, Ire1 molecules cluster in the ER membrane into discrete foci of higher-order oligomers, to which unspliced HAC1 mRNA is recruited by means of a conserved bipartite targeting element contained in the 3' untranslated region. Disruption of either Ire1 clustering or HAC1 mRNA recruitment impairs UPR signalling. The HAC1 3' untranslated region element is sufficient to target other mRNAs to Ire1 foci, as long as their translation is repressed. Translational repression afforded by the intron fulfils this requirement for HAC1 mRNA. Recruitment of mRNA to signalling centres provides a new paradigm for the control of eukaryotic gene expression.
authors.affiliation: Department of Biochemistry and Biophysics, University of California at San Francisco, San Francisco, California 94158-2517, USA. Tomas.Aragon@ucsf.edu
authors.forename: Tomás
authors.initials: T
authors.lastname: Aragón
authors.forename: Eelco
authors.initials: E
authors.lastname: van Anken
authors.forename: David
authors.initials: D
authors.lastname: Pincus
authors.forename: Iana M
authors.initials: IM
authors.lastname: Serafimova
authors.forename: Alexei V
authors.initials: AV
authors.lastname: Korennykh
authors.forename: Claudia A
authors.initials: CA
authors.lastname: Rubio
authors.forename: Peter
authors.initials: P
authors.lastname: Walter
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D050976:Basic-Leucine Zipper Transcription Factors / Q000235:genetics; D017124:Conserved Sequence; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D015966:Gene Expression Regulation, Fungal / Q000235:genetics; D007438:Introns / Q000235:genetics; D008562:Membrane Glycoproteins / Q000378:metabolism; D014176:Protein Biosynthesis; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D012326:RNA Splicing; D012331:RNA, Fungal / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism*; D012097:Repressor Proteins / Q000235:genetics; D012441:Saccharomyces cerevisiae / Q000166:cytology* / Q000235:genetics*; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013312:Stress, Physiological / Q000235:genetics
chemical_list: D020413:3' Untranslated Regions; D050976:Basic-Leucine Zipper Transcription Factors; C091341:HAC1 protein, S cerevisiae; D008562:Membrane Glycoproteins; D012331:RNA, Fungal; D012333:RNA, Messenger; D012097:Repressor Proteins; D029701:Saccharomyces cerevisiae Proteins; C082863:IRE1 protein, S cerevisiae; D017346:Protein Serine-Threonine Kinases