Open AccessInhibition of IRE1α RNase activity reduces NLRP3 inflammasome assembly and processing of pro-IL1β
Author(s) -
Aaron Talty,
Shane Deegan,
Mila Ljujić,
Katarzyna Mnich,
Serika D. Naicker,
Dagmar Quandt,
Qingping Zeng,
John B. Patterson,
Adrienne M. Gorman,
Matthew D. Griffin,
Afshin Samali,
Susan E. Logue
Publication year - 2019
Publication title -
cell death and disease
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.482
H-Index - 111
ISSN - 2041-4889
DOI - 10.1038/s41419-019-1847-z
Subject(s) - inflammasome , microbiology and biotechnology , aim2 , innate immune system , signal transduction , caspase 1 , priming (agriculture) , pyroptosis , chemistry , biology , inflammation , immune system , immunology , botany , germination
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-1β 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 IRE1α, a key component of the Unfolded Protein Response, contributes to assembly of the NLRP3 inflammasome. Blockade of IRE1α RNase signaling lowered NLRP3 inflammasome assembly, caspase-1 activation and pro-IL-1β processing. These results underscore both the importance and potential therapeutic relevance of targeting IRE1α signaling in conditions of excessive inflammasome formation.