Cryo-sensitive aggregation triggers NLRP3 inflammasome assembly in cryopyrin-associated periodic syndrome.

Abstract

Cryopyrin-associated periodic syndrome (CAPS) is an autoinflammatory syndrome caused by mutations of NLRP3 gene encoding cryopyrin. Familial cold autoinflammatory syndrome, 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.

• Authors: Tadayoshi Karasawa, Takanori Komada, Naoya Yamada, Emi Aizawa, Yoshiko Mizushina, Sachiko Watanabe, Chintogtokh Baatarjav, Takayoshi Matsumura, Masafumi Takahashi
• Journal: eLife (Elife) Vol. 11 (05 26 2022) ISSN: 2050-084X [Electronic] England
• PMID: 35616535 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2022, Karasawa et al.

Chemical References

• Carrier Proteins
• Inflammasomes
• Interleukin-1beta
• NLR Family, Pyrin Domain-Containing 3 Protein
• Caspase 1

Topics

• Carrier Proteins (genetics)
• Caspase 1 (genetics)
• Cryopyrin-Associated Periodic Syndromes (genetics)
• Humans
• Inflammasomes (metabolism)
• Interleukin-1beta (metabolism)
• NLR Family, Pyrin Domain-Containing 3 Protein (genetics)