The unfolded protein response signals through high-order assembly of Ire1
Open accessAbstract
Aberrant folding of proteins in the endoplasmic reticulum activates the bifunctional transmembrane kinase/endoribonuclease Ire1. Ire1 excises an intron from HAC1 messenger RNA in yeasts and Xbp1 messenger RNA in metozoans encoding homologous transcription factors. This non-conventional mRNA splicing event initiates the unfolded protein response, a transcriptional program that relieves the endoplasmic reticulum stress. Here we show that oligomerization is central to Ire1 function and is an intrinsic attribute of its cytosolic domains. We obtained the 3.2-A crystal structure of the oligomer of the Ire1 cytosolic domains in complex with a kinase inhibitor that acts as a potent activator of the Ire1 RNase. The structure reveals a rod-shaped assembly that has no known precedence among kinases. This assembly positions the kinase domain for trans-autophosphorylation, orders the RNase domain, and creates an interaction surface for binding of the mRNA substrate. Activation of Ire1 through oligomerization expands the mechanistic repertoire of kinase-based signalling receptors.
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In response to ER stress, activated Ire1 cleaves HAC1 mRNA in yeast in a spliceosome-independent manner, excising intron sequences.
“In response to ER stress, the activated Ire1 cleaves HAC1 mRNA in yeast in a spliceosome-independent manner, thereby excising the intron sequences [50].”
From Disruption of the UPC2 Gene Enhances Fluconazole Antifungal Activity by Inhibiting HAC1 mRNA Splicing in Candida albicans (2026) · cites this paper as [50]
In yeast, Ire1 initiates UPR signaling through unconventional splicing of HAC1 mRNA, producing active transcription factor Hac1, which induces UPR target genes.
“In yeast, the ER transmembrane kinase/ribonuclease Ire1 initiates UPR signaling through the unconventional splicing of HAC1 mRNA, resulting in the production of the active transcription factor Hac1, which subsequently induces the expression of UPR target genes [48,50].”
From Disruption of the UPC2 Gene Enhances Fluconazole Antifungal Activity by Inhibiting HAC1 mRNA Splicing in Candida albicans (2026) · cites this paper as [50]
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“In response to ER stress, the activated Ire1 cleaves HAC1 mRNA in yeast in a spliceosome-independent manner, thereby excising the intron sequences [50].”
- Authors
- Korennykh, A. V., Egea, P. F., Korostelev, A. A., Finer-Moore, J., Zhang, C., Shokat, K. M., Stroud, R. M., & Walter, P.
- Affiliations
- University of California, San Francisco (US)
- University of California, Santa Cruz (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Korennykh, Alexei V.
- ORCID
- Venue
- Nature
- Published
- 2008-12-14
- Volume
- 457
- Issue
- 7230
- Pages
- 687-693
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC2846394
- OpenAlex
- W1986290768
- Cited by
- 656
- References
- 39
- Citations by year
- 2026: 11 · 2025: 20 · 2024: 36 · 2023: 35 · 2022: 37 · 2021: 45 · 2020: 44 · 2019: 56 · 2018: 42 · 2017: 34 · 2016: 21 · 2015: 39 · 2014: 57 · 2013: 42 · 2012: 48
- FWCI
- 13.12
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- National Institute of General Medical Sciences (R01 GM60641, R01GM060641)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Endoplasmic Reticulum Stress and Disease
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
- Keywords
- unfolded protein response, IRE1, protein oligomerization, endoplasmic reticulum stress, XBP1, kinase domain, endoribonuclease, trans-autophosphorylation, 3' untranslated region, protein misfolding
- MeSH terms
- Binding Sites, Cytosol, Enzyme Activation, Introns, Membrane Glycoproteins, Models, Molecular, Phosphorylation, Protein Binding, Protein Denaturation, Repressor Proteins, Ribonucleases, Saccharomyces cerevisiae, Protein Serine-Threonine Kinases, Protein Structure, Tertiary, Protein Folding, Crystallography, X-Ray, Protein Structure, Quaternary, Saccharomyces cerevisiae Proteins, Protein Kinase Inhibitors, Basic-Leucine Zipper Transcription Factors, Protein Multimerization
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