Inhibition of IRE1 alpha RNase activity reduces NLRP3 inflammasome assembly and processing of pro-IL1 beta
Authors
Talty, AaronDeegan, Shane
Ljujić, Mila
Mnich, Katarzyna
Naicker, Serika D.
Quandt, Dagmar
Zeng, Qingping
Patterson, John B.
Gorman, Adrienne M.
Griffin, Matthew D.
Samali, Afshin
Logue, Susan E.
Article (Published version)
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The inflammasome is a multiprotein complex assembled in response to Pathogen Associated Molecular Patterns (PAMPs) and Danger Associated Molecular Patterns (DAMPS). Inflammasome activation occurs through a two-step mechanism, with the first signal facilitating priming of inflammasome components while the second signal triggers complex assembly. Once assembled, the inflammasome recruits and activates pro-caspase-1, which in turn processes pro-interleukin (IL)-18 and pro-IL-1 beta into their bio-active forms. Owing to its key role in the regulation of innate immune responses, the inflammasome has emerged as a therapeutic target for the treatment of inflammatory conditions. In this study we demonstrate that IRE1 alpha, a key component of the Unfolded Protein Response, contributes to assembly of the NLRP3 inflammasome. Blockade of IRE1 alpha RNase signaling lowered NLRP3 inflammasome assembly, caspase-1 activation and pro-IL-1 beta processing. These results underscore both the importance a...nd potential therapeutic relevance of targeting IRE1 alpha signaling in conditions of excessive inflammasome formation.
Source:
Cell Death & Disease, 2019, 10Publisher:
- Nature Publishing Group, London
Funding / projects:
- Science Foundation Ireland
- Irish Government
- Health Research Board [HRA-POR-2014-643]
- Science Foundation Ireland (SFI) grant under the European Regional Development Fund [13/RC/2073]
- SFI Starting Investigator Grant [15/SIRG/3528]
- Canada Research Chairs program
- Irish Research Council Fellowship [EBPPG/2014/74]
- European Commission [Horizon 2020 Collaborative Health Project NEPHSTROM] [634086]
- European Commission [FP7 Collaborative Health Project VISICORT] [602470]
- Science Foundation Ireland [REMEDI Strategic Research Cluster] [09/SRC-B1794]
- CURAM Research Centre [13/RC/2073]
- Molecular Medicine Ireland Clinical and Translational Research Scholarship - Irish Government's Programme for Research in Third Level Institutions, Cycle5
- College of Medicine, Nursing and Health Sciences of the National University of Ireland Galway
- NUI Galway
DOI: 10.1038/s41419-019-1847-z
ISSN: 2041-4889
PubMed: 31417078
WoS: 000481964900001
Scopus: 2-s2.0-85070746018
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Institut za molekularnu genetiku i genetičko inženjerstvoTY - JOUR AU - Talty, Aaron AU - Deegan, Shane AU - Ljujić, Mila AU - Mnich, Katarzyna AU - Naicker, Serika D. AU - Quandt, Dagmar AU - Zeng, Qingping AU - Patterson, John B. AU - Gorman, Adrienne M. AU - Griffin, Matthew D. AU - Samali, Afshin AU - Logue, Susan E. PY - 2019 UR - https://imagine.imgge.bg.ac.rs/handle/123456789/1201 AB - The inflammasome is a multiprotein complex assembled in response to Pathogen Associated Molecular Patterns (PAMPs) and Danger Associated Molecular Patterns (DAMPS). Inflammasome activation occurs through a two-step mechanism, with the first signal facilitating priming of inflammasome components while the second signal triggers complex assembly. Once assembled, the inflammasome recruits and activates pro-caspase-1, which in turn processes pro-interleukin (IL)-18 and pro-IL-1 beta into their bio-active forms. Owing to its key role in the regulation of innate immune responses, the inflammasome has emerged as a therapeutic target for the treatment of inflammatory conditions. In this study we demonstrate that IRE1 alpha, a key component of the Unfolded Protein Response, contributes to assembly of the NLRP3 inflammasome. Blockade of IRE1 alpha RNase signaling lowered NLRP3 inflammasome assembly, caspase-1 activation and pro-IL-1 beta processing. These results underscore both the importance and potential therapeutic relevance of targeting IRE1 alpha signaling in conditions of excessive inflammasome formation. PB - Nature Publishing Group, London T2 - Cell Death & Disease T1 - Inhibition of IRE1 alpha RNase activity reduces NLRP3 inflammasome assembly and processing of pro-IL1 beta VL - 10 DO - 10.1038/s41419-019-1847-z ER -
@article{ author = "Talty, Aaron and Deegan, Shane and Ljujić, Mila and Mnich, Katarzyna and Naicker, Serika D. and Quandt, Dagmar and Zeng, Qingping and Patterson, John B. and Gorman, Adrienne M. and Griffin, Matthew D. and Samali, Afshin and Logue, Susan E.", year = "2019", abstract = "The inflammasome is a multiprotein complex assembled in response to Pathogen Associated Molecular Patterns (PAMPs) and Danger Associated Molecular Patterns (DAMPS). Inflammasome activation occurs through a two-step mechanism, with the first signal facilitating priming of inflammasome components while the second signal triggers complex assembly. Once assembled, the inflammasome recruits and activates pro-caspase-1, which in turn processes pro-interleukin (IL)-18 and pro-IL-1 beta into their bio-active forms. Owing to its key role in the regulation of innate immune responses, the inflammasome has emerged as a therapeutic target for the treatment of inflammatory conditions. In this study we demonstrate that IRE1 alpha, a key component of the Unfolded Protein Response, contributes to assembly of the NLRP3 inflammasome. Blockade of IRE1 alpha RNase signaling lowered NLRP3 inflammasome assembly, caspase-1 activation and pro-IL-1 beta processing. These results underscore both the importance and potential therapeutic relevance of targeting IRE1 alpha signaling in conditions of excessive inflammasome formation.", publisher = "Nature Publishing Group, London", journal = "Cell Death & Disease", title = "Inhibition of IRE1 alpha RNase activity reduces NLRP3 inflammasome assembly and processing of pro-IL1 beta", volume = "10", doi = "10.1038/s41419-019-1847-z" }
Talty, A., Deegan, S., Ljujić, M., Mnich, K., Naicker, S. D., Quandt, D., Zeng, Q., Patterson, J. B., Gorman, A. M., Griffin, M. D., Samali, A.,& Logue, S. E.. (2019). Inhibition of IRE1 alpha RNase activity reduces NLRP3 inflammasome assembly and processing of pro-IL1 beta. in Cell Death & Disease Nature Publishing Group, London., 10. https://doi.org/10.1038/s41419-019-1847-z
Talty A, Deegan S, Ljujić M, Mnich K, Naicker SD, Quandt D, Zeng Q, Patterson JB, Gorman AM, Griffin MD, Samali A, Logue SE. Inhibition of IRE1 alpha RNase activity reduces NLRP3 inflammasome assembly and processing of pro-IL1 beta. in Cell Death & Disease. 2019;10. doi:10.1038/s41419-019-1847-z .
Talty, Aaron, Deegan, Shane, Ljujić, Mila, Mnich, Katarzyna, Naicker, Serika D., Quandt, Dagmar, Zeng, Qingping, Patterson, John B., Gorman, Adrienne M., Griffin, Matthew D., Samali, Afshin, Logue, Susan E., "Inhibition of IRE1 alpha RNase activity reduces NLRP3 inflammasome assembly and processing of pro-IL1 beta" in Cell Death & Disease, 10 (2019), https://doi.org/10.1038/s41419-019-1847-z . .