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Cell Rep. 2014 Nov 6;9(3):850-8. doi: 10.1016/j.celrep.2014.09.016. Epub 2014 Oct 30.

Ire1 has distinct catalytic mechanisms for XBP1/HAC1 splicing and RIDD.

Author information

1
Division of Biological Sciences, Section of Molecular Biology, UCSD, La Jolla, CA 92093-0377, USA.
2
Department of Radiation Oncology, Stanford School of Medicine, Stanford, CA 94305-5152, USA.
3
Division of Biological Sciences, Section of Molecular Biology, UCSD, La Jolla, CA 92093-0377, USA. Electronic address: niwa@ucsd.edu.

Abstract

An evolutionarily conserved unfolded protein response (UPR) component, IRE1, cleaves XBP1/HAC1 introns in order to generate spliced mRNAs that are translated into potent transcription factors. IRE1 also cleaves endoplasmic-reticulum-associated RNAs leading to their decay, an activity termed regulated IRE1-dependent decay (RIDD); however, the mechanism by which IRE1 differentiates intron cleavage from RIDD is not well understood. Using in vitro experiments, we found that IRE1 has two different modes of action: XBP1/HAC1 is cleaved by IRE1 subunits acting cooperatively within IRE1 oligomers, whereas a single subunit of IRE1 performs RIDD without cooperativity. Furthermore, these distinct activities can be separated by complementation of catalytically inactive IRE1 RNase and mutations at oligomerization interfaces. Using an IRE1 RNase inhibitor, STF-083010, selective inhibition of XBP1 splicing indicates that XBP1 promotes cell survival, whereas RIDD leads to cell death, revealing modulation of IRE1 activities as a drug-development strategy.

PMID:
25437541
PMCID:
PMC4486022
DOI:
10.1016/j.celrep.2014.09.016
[Indexed for MEDLINE]
Free PMC Article

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