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Phosphoregulation of Ire1 RNase splicing activity
Filippo Prischi1, Piotr R Nowak1, Marta Carrara1
1Department of Life Sciences, Centre for Structural Biology, Sir Ernst Chain Building, Imperial College London, London SW7 2AZ, UK.
Nature Communications
|April 8, 2014
Summary
Phosphorylation of the Ire1 enzyme
Area of Science:
- Cellular Biology
- Molecular Biology
- Biochemistry
Background:
- Endoplasmic reticulum stress triggers the unfolded protein response (UPR).
- Ire1, a kinase and RNase enzyme, is central to UPR activation.
- Ire1's specific Xbp1 mRNA splicing is crucial for UPR.
Purpose of the Study:
- Investigate the impact of phosphorylation on Ire1's RNase splicing activity.
- Determine how specific phosphorylation sites affect Ire1 function.
- Elucidate the role of phosphorylation in Ire1-mediated UPR.
Main Methods:
- Isolation of distinct phosphorylated Ire1 species.
- In vitro assessment of Ire1 RNase splicing activity.
- In vivo analysis of Ire1 mutants in cellular UPR models.
Main Results:
- Phosphorylation within the Ire1 kinase activation loop enhances RNase splicing in vitro.
- Ire1 mutants lacking activation loop phosphorylation exhibit reduced Xbp1 splicing and increased promiscuous RNase activity.
- These findings link kinase activity to RNase activation.
Conclusions:
- Phosphorylation of the Ire1 activation loop is a key regulatory step in UPR.
- This phosphorylation directly modulates Ire1's RNase activity.
- Understanding this mechanism is vital for UPR pathway research.
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