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The molecular basis for selective inhibition of unconventional mRNA splicing by an IRE1-binding small molecule
Open accessAbstract
IRE1 couples endoplasmic reticulum unfolded protein load to RNA cleavage events that culminate in the sequence-specific splicing of the Xbp1 mRNA and in the regulated degradation of diverse membrane-bound mRNAs. We report on the identification of a small molecule inhibitor that attains its selectivity by forming an unusually stable Schiff base with lysine 907 in the IRE1 endonuclease domain, explained by solvent inaccessibility of the imine bond in the enzyme-inhibitor complex. The inhibitor (abbreviated 4μ8C) blocks substrate access to the active site of IRE1 and selectively inactivates both Xbp1 splicing and IRE1-mediated mRNA degradation. Surprisingly, inhibition of IRE1 endonuclease activity does not sensitize cells to the consequences of acute endoplasmic reticulum stress, but rather interferes with the expansion of secretory capacity. Thus, the chemical reactivity and sterics of a unique residue in the endonuclease active site of IRE1 can be exploited by selective inhibitors to interfere with protein secretion in pathological settings.
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Harding, H. P., Zhang, Y., Bertolotti, A., Zeng, H., & Ron, D. (2000) · Molecular Cell · doi:10.1016/s1097-2765(00)80330-5 · Cited by 2,021
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Singh, J., Petter, R. C., Baillie, T. A., & Whitty, A. (2011) · Nature Reviews Drug Discovery · doi:10.1038/nrd3410 · Cited by 1,873
TLR activation of the transcription factor XBP1 regulates innate immune responses in macrophages
Martinon, F., Chen, X., Lee, A.-H., & Glimcher, L. H. (2010) · Nature Immunology · doi:10.1038/ni.1857 · Cited by 996
The unfolded protein response signals through high-order assembly of Ire1
Korennykh, A. V., Egea, P. F., Korostelev, A. A., Finer-Moore, J., Zhang, C., Shokat, K. M., Stroud, R. M., & Walter, P. (2009) · Nature · doi:10.1038/nature07661 · Cited by 656
Todd, D. J., McHeyzer-Williams, L. J., Kowal, C., Lee, A.-H., Volpe, B. T., Diamond, B., McHeyzer-Williams, M. G., & Glimcher, L. H. (2009) · Journal of Experimental Medicine · doi:10.1084/jem.20090738 · Cited by 233
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Endoplasmic reticulum stress signalling-from basic mechanisms to clinical applications
Almanza, A., Carlesso, A., Chintha, C., Creedican, S., Doultsinos, D., Leuzzi, B., Luís, A., McCarthy, N., Montibeller, L., More, S., et al. (2019) · The FEBS Journal · doi:10.1111/febs.14608 · Cited by 1,034
Tumorigenic and Immunosuppressive Effects of Endoplasmic Reticulum Stress in Cancer
Cubillos-Ruiz, J. R., Bettigole, S. E., & Glimcher, L. H. (2017) · Cell · doi:10.1016/j.cell.2016.12.004 · Cited by 895
Endoplasmic Reticulum Stress Sensing in the Unfolded Protein Response
Gardner, B. M., Pincus, D., Gotthardt, K., Gallagher, C. M., & Walter, P. (2013) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a013169 · Cited by 721
Opposing unfolded-protein-response signals converge on death receptor 5 to control apoptosis
Lu, M., Lawrence, D. A., Marsters, S., Acosta-Alvear, D., Kimmig, P., Mendez, A. S., Paton, A. W., Paton, J. C., Walter, P., & Ashkenazi, A. (2014) · Science · doi:10.1126/science.1254312 · Cited by 567
Endoplasmic reticulum dysfunction in neurological disease
Roussel, B. D., Kruppa, A. J., Miranda, E., Crowther, D. C., Lomas, D. A., & Marciniak, S. J. (2013) · The Lancet Neurology · doi:10.1016/s1474-4422(12)70238-7 · Cited by 441
Metadata
- Authors
- Cross, B. C. S., Bond, P. J., Sadowski, P. G., Jha, B. K., Zak, J., Goodman, J. M., Silverman, R. H., Neubert, T. A., Baxendale, I. R., Ron, D., & Harding, H. P.
- Venue
- Proceedings of the National Academy of Sciences
- Published
- 2012-02-06
- Volume
- 109
- Issue
- 15
- Pages
- E869-78
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- OpenAlex
- W2158837517
- Cited by
- 591
- References
- 5
- FWCI
- 15.85
- Type
- journal article
- Language
- en
- Open access
- green
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- Cross, B. C. S., Bond, P. J., Sadowski, P. G., Jha, B. K., Zak, J., Goodman, J. M., Silverman, R. H., Neubert, T. A., Baxendale, I. R., Ron, D., & Harding, H. P. (2012). The molecular basis for selective inhibition of unconventional mRNA splicing by an IRE1-binding small molecule. Proceedings of the National Academy of Sciences. https://doi.org/10.1073/pnas.1115623109
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Contains information from the Semantic Scholar Academic Graph Datasets, made available under the ODC Attribution License (ODC-BY 1.0).
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