mRNA Targeting to ER Stress Signaling Sites

Deficiencies in the protein folding capacity of the endoplasmic reticulum (ER) in all eucaryotic cells lead to ER stress and triggers the unfolded protein response (UPR)1–3. ER stress is sensed by Ire1, a transmembrane kinase/endoribonuclease, which initiates the non-conventional splicing of the mRNA encoding a key transcription activator, Hac1 in yeast or XBP-1 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 (5′UTR)4. After excision of the intron, tRNA ligase joins the severed exons5,6, lifting the translational block and allowing synthesis of Hac1 from the spliced HAC1 mRNA to ensue4. Hac1 in turn drives the UPR gene expression program comprising 7–8% of the yeast genome7 to counteract ER stress. We show here that upon 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 (3′UTR). Disruption of either Ire1 clustering or of HAC1 mRNA recruitment impairs UPR signaling. The HAC1 3′UTR element is sufficient to target other mRNAs to Ire1 foci, as long as their translation is repressed. Translational repression afforded by the intron fulfills this requirement for HAC1 mRNA. Recruitment of mRNA to signaling centers provides a new paradigm for the control of eukaryotic gene expression.