1. Cryo-sensitive aggregation triggers NLRP3 inflammasome assembly in cryopyrin-associated periodic syndrome
- Author
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Naoya Yamada, Tadayoshi Karasawa, Takanori Komada, Yoshiko Mizushina, Masafumi Takahashi, Takayoshi Matsumura, Emi Aizawa, Chintogtokh Baatarjav, and Sachiko Watanabe
- Subjects
Inflammasomes ,Interleukin-1beta ,Mutant ,Inflammation ,General Biochemistry, Genetics and Molecular Biology ,Familial Cold Autoinflammatory Syndrome ,NLR Family, Pyrin Domain-Containing 3 Protein ,medicine ,Humans ,General Immunology and Microbiology ,integumentary system ,Chemistry ,General Neuroscience ,Caspase 1 ,Cryopyrin-associated periodic syndrome ,Inflammasome ,General Medicine ,Autoinflammatory Syndrome ,medicine.disease ,Cryopyrin-Associated Periodic Syndromes ,Cell biology ,Efflux ,medicine.symptom ,Carrier Proteins ,Function (biology) ,medicine.drug - Abstract
Cryopyrin-associated periodic syndrome (CAPS) is an autoinflammatory syndrome caused by mutations of NLRP3, which was originally identified as 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 indispensable 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.
- Published
- 2021