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Talty, A,Deegan, S,Ljujic, M,Mnich, K,Naicker, SD,Quandt, D,Zeng, QP,Patterson, JB,Gorman, AM,Griffin, MD,Samali, A,Logue, SE
2019
August
Cell Death & Disease
Inhibition of IRE1 alpha RNase activity reduces NLRP3 inflammasome assembly and processing of pro-IL1 beta
Published
Optional Fields
THIOREDOXIN-INTERACTING PROTEIN TRANSMEMBRANE PROTEIN NALP3 INFLAMMASOME MESSENGER-RNAS CUTTING EDGE CELL-DEATH ACTIVATION STRESS ER REQUIRES
10
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.
10.1038/s41419-019-1847-z
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