NLRP3 leucine-rich repeats control induced and spontaneous inflammasome activation in cryopyrin-associated periodic syndrome.

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Version: Final published version
License: CC BY 4.0
Serval ID
serval:BIB_17138F05CB5E
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
NLRP3 leucine-rich repeats control induced and spontaneous inflammasome activation in cryopyrin-associated periodic syndrome.
Journal
The Journal of allergy and clinical immunology
Author(s)
Theodoropoulou K., Spel L., Zaffalon L., Delacrétaz M., Hofer M., Martinon F.
ISSN
1097-6825 (Electronic)
ISSN-L
0091-6749
Publication state
Published
Issued date
01/2023
Peer-reviewed
Oui
Volume
151
Number
1
Pages
222-232.e9
Language
english
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Abstract
The cryopyrin-associated periodic syndromes (CAPS) comprise a group of rare autoinflammatory diseases caused by gain-of-function mutations in the NLRP3 gene. NLRP3 contains a leucine-rich repeats (LRR) domain with a highly conserved exonic organization that is subjected to extensive alternative splicing. Aberrant NLRP3 inflammasome assembly in CAPS causes chronic inflammation; however, the mechanisms regulating inflammasome function remain unclear.
We aimed to elucidate the mechanisms regulating NLRP3-mediated autoinflammation in human disease, characterizing the role of LRR in inflammasome activation.
We analyzed sequence read archive data to characterize the pattern of NLRP3 splicing in human monocytes and investigated the role of each LRR-coding exon in inflammasome regulation in genetically modified U937 cells representing CAPS and healthy conditions.
We detected a range of NLRP3 splice variants in human primary cells and monocytic cell lines, including 2 yet-undescribed splice variants. We observe that lipopolysaccharides affect the abundance of certain splice variants, suggesting that they may regulate NLRP3 activation by affecting alternative splicing. We showed that exons 4, 5, 7, and 9 are essential for inflammasome function, both in the context of wild-type NLRP3 activation by the agonist molecule nigericin and in a model of CAPS-mediated NLRP3 inflammasome assembly. Moreover, the SGT1-NLRP3 interaction is decreased in nonfunctional variants, suggesting that alternative splicing may regulate the recruitment of proteins that facilitate inflammasome assembly.
These findings demonstrate the contribution of the LRR domain in inflammasome function and suggest that navigating LRR exon usage within NLRP3 is sufficient to dampen inflammasome assembly in CAPS.
Keywords
Humans, Inflammasomes/metabolism, Cryopyrin-Associated Periodic Syndromes/genetics, NLR Family, Pyrin Domain-Containing 3 Protein/genetics, NLR Family, Pyrin Domain-Containing 3 Protein/metabolism, Leucine/genetics, Gain of Function Mutation, CAPS, Inflammasome, LRR, NLRP3, alternative splicing, autoinflammatory disease, cryopyrin, cryopyrinopathies
Pubmed
Web of science
Open Access
Yes
Create date
20/09/2022 13:40
Last modification date
14/04/2023 5:54
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