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

Autor:	Karasawa T; Division of Inflammation Research, Center for Molecular Medicine, Jichi Medical University, Tochigi, Japan., Komada T; Division of Inflammation Research, Center for Molecular Medicine, Jichi Medical University, Tochigi, Japan., Yamada N; Division of Inflammation Research, Center for Molecular Medicine, Jichi Medical University, Tochigi, Japan., Aizawa E; Division of Inflammation Research, Center for Molecular Medicine, Jichi Medical University, Tochigi, Japan., Mizushina Y; Division of Inflammation Research, Center for Molecular Medicine, Jichi Medical University, Tochigi, Japan., Watanabe S; Division of Inflammation Research, Center for Molecular Medicine, Jichi Medical University, Tochigi, Japan., Baatarjav C; Division of Inflammation Research, Center for Molecular Medicine, Jichi Medical University, Tochigi, Japan., Matsumura T; Division of Inflammation Research, Center for Molecular Medicine, Jichi Medical University, Tochigi, Japan., Takahashi M; Division of Inflammation Research, Center for Molecular Medicine, Jichi Medical University, Tochigi, Japan.
Jazyk:	angličtina
Zdroj:	ELife [Elife] 2022 May 26; Vol. 11. Date of Electronic Publication: 2022 May 26.
DOI:	10.7554/eLife.75166
Abstrakt:	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, Ca 2+ was necessary for mutated NLRP3-mediated inflammasome assembly. Notably, Ca 2+ influx was induced during mutated NLRP3-mediated inflammasome assembly. Furthermore, caspase-1 inhibition prevented Ca 2+ influx and inflammasome assembly induced by the mutated NLRP3, suggesting a feed-forward Ca 2+ influx loop triggered by mutated NLRP3. Thus, the mutated NLRP3 forms cryo-sensitive aggregates to promote inflammasome assembly distinct from canonical NLRP3 inflammasome activation. Competing Interests: TK, TK, NY, EA, YM, SW, CB, TM, MT No competing interests declared (© 2022, Karasawa et al.)
Databáze:	MEDLINE
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