Cryo-sensitive aggregation triggers NLRP3 inflammasome assembly in cryopyrin-associated periodic syndrome
- Jichi Medical University, Japan
Abstract
Cryopyrin-associated periodic syndrome (CAPS) is an autoinflammatory syndrome caused by mutations of NLRP3 gene encoding cryopyrin. Familial cold autoinflammatory syndrome (FCAS), the mildest form of CAPS, is characterized by cold-induced inflammation induced by the overproduction of IL-1β. However, the molecular mechanism of how mutated NLRP3 causes inflammasome activation in CAPS remains unclear. Here, we found that CAPS-associated NLRP3 mutants form cryo-sensitive aggregates that function as a scaffold for inflammasome activation. Cold exposure promoted inflammasome assembly and subsequent IL-1β release triggered by mutated NLRP3. While K+ efflux was dispensable, Ca2+ was necessary for mutated NLRP3-mediated inflammasome assembly. Notably, Ca2+ influx was induced during mutated NLRP3-mediated inflammasome assembly. Furthermore, caspase-1 inhibition prevented Ca2+ influx and inflammasome assembly induced by the mutated NLRP3, suggesting a feed-forward Ca2+ influx loop triggered by mutated NLRP3. Thus, the mutated NLRP3 forms cryo-sensitive aggregates to promote inflammasome assembly distinct from canonical NLRP3 inflammasome activation.
Data availability
All data generated or analyzed during this study are included in the manuscript and supporting file; Source Data files have been provided for Figures 1-8.
Article and author information
Author details
Tadayoshi Karasawa
Masafumi Takahashi
Funding
Japan Society for the Promotion of Science (18K08112)
- Masafumi Takahashi
Japan Society for the Promotion of Science (21K08114)
- Masafumi Takahashi
Japan Society for the Promotion of Science (16H01395)
- Masafumi Takahashi
Ichiro Kanehara Foundation for the Promotion of Medical Sciences and Medical Care
- Tadayoshi Karasawa
Japan Agency for Medical Research and Development
- Masafumi Takahashi
Ministry of Education, Culture, Sports, Science and Technology
- Masafumi Takahashi
We declare that the funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
© 2022, Karasawa et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Cryo-sensitive aggregation triggers NLRP3 inflammasome assembly in cryopyrin-associated periodic syndrome
eLife 11:e75166.
https://doi.org/10.7554/eLife.75166
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