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Elife. 2014 Dec 30;3:e05031. doi: 10.7554/eLife.05031.

Specificity in endoplasmic reticulum-stress signaling in yeast entails a step-wise engagement of HAC1 mRNA to clusters of the stress sensor Ire1.

Author information

1
Division of Genetics and Cell Biology, San Raffaele Scientific Institute, Milan, Italy.
2
Department of Biochemistry and Biophysics, Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, United States.
3
Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, United States.
4
Department of Gene Therapy and Gene Regulation, Center for Applied Medical Research, Pamplona, Spain.

Abstract

Insufficient protein-folding capacity in the endoplasmic reticulum (ER) induces the unfolded protein response (UPR). In the ER lumen, accumulation of unfolded proteins activates the transmembrane ER-stress sensor Ire1 and drives its oligomerization. In the cytosol, Ire1 recruits HAC1 mRNA, mediating its non-conventional splicing. The spliced mRNA is translated into Hac1, the key transcription activator of UPR target genes that mitigate ER-stress. In this study, we report that oligomeric assembly of the ER-lumenal domain is sufficient to drive Ire1 clustering. Clustering facilitates Ire1's cytosolic oligomeric assembly and HAC1 mRNA docking onto a positively charged motif in Ire1's cytosolic linker domain that tethers the kinase/RNase to the transmembrane domain. By the use of a synthetic bypass, we demonstrate that mRNA docking per se is a pre-requisite for initiating Ire1's RNase activity and, hence, splicing. We posit that such step-wise engagement between Ire1 and its mRNA substrate contributes to selectivity and efficiency in UPR signaling.

KEYWORDS:

S. cerevisiae; biochemistry; cell biology; endoplasmic reticulum; mRNA processing; mRNA targeting; stress signaling; unfolded protein response

PMID:
25549299
PMCID:
PMC4279078
DOI:
10.7554/eLife.05031
[Indexed for MEDLINE]
Free PMC Article

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