NOD-,LRR-,and pyrin domain-containing 3(NLRP3)is a cytosolic innate immune sensor of cellular stress signals,triggered by infection and sterile inflammation.Upon detection of an activating stimulus,NLRP3 transitions f...NOD-,LRR-,and pyrin domain-containing 3(NLRP3)is a cytosolic innate immune sensor of cellular stress signals,triggered by infection and sterile inflammation.Upon detection of an activating stimulus,NLRP3 transitions from an inactive homo-oligomeric multimer into an active multimeric inflammasome,which promotes the helical oligomeric assembly of the adaptor molecule ASC.ASC oligomers provide a platform for caspase-1 activation,leading to the proteolytic cleavage and activation of proinflammatory cytokines in the IL-1 family and gasdermin D,which can induce a lytic form of cell death.Recent studies investigating both the cellular requirement for NLRP3 activation and the structure of NLRP3 have revealed the complex regulation of NLRP3 and the multiple steps involved in its activation.This review presents a perspective on the biochemical and cellular processes controlling the assembly of the NLRP3 inflammasome with particular emphasis on structural regulation and the role of organelles.We also highlight the latest research on metabolic control of this inflammatory pathway and discuss promising clinical targets for intervention.展开更多
基金Figures were designed using Biorender and Affinity designer.EL received funding from the European Union’s Horizon 2020 Research and Innovation Program under grant No.848146(To_Aition)EL is further funded by the Deutsche Forschungsgemeinschaft(DFG,German Research Foundation)under Germany’s Excellence Strategy-EXC2151-390873048 and has received funding through the DFG SFB1454(432325352)+1 种基金SFB1402(414786233),TRR237(369799452),and GRK2168(272482170)This work was further supported by the Helmholtz-Gemeinschaft,Zukunftsthema“Immunology and Inflammation”(ZT-0027).
文摘NOD-,LRR-,and pyrin domain-containing 3(NLRP3)is a cytosolic innate immune sensor of cellular stress signals,triggered by infection and sterile inflammation.Upon detection of an activating stimulus,NLRP3 transitions from an inactive homo-oligomeric multimer into an active multimeric inflammasome,which promotes the helical oligomeric assembly of the adaptor molecule ASC.ASC oligomers provide a platform for caspase-1 activation,leading to the proteolytic cleavage and activation of proinflammatory cytokines in the IL-1 family and gasdermin D,which can induce a lytic form of cell death.Recent studies investigating both the cellular requirement for NLRP3 activation and the structure of NLRP3 have revealed the complex regulation of NLRP3 and the multiple steps involved in its activation.This review presents a perspective on the biochemical and cellular processes controlling the assembly of the NLRP3 inflammasome with particular emphasis on structural regulation and the role of organelles.We also highlight the latest research on metabolic control of this inflammatory pathway and discuss promising clinical targets for intervention.
