IKKβ binds NLRP3 providing a shortcut to inflammasome activation for rapid immune responses

Dear Editor,A rapid immune response to signals released from pathogens and injuries is critical for maintaining tissue integrity and restoring homeostasis.This response is largely mediated by the concerted action of pattern recognition receptors(PRRs).Such cooperativity has been described for Toll-like receptors(TLRs)and NACHT,LRR,and pyrin domain-containing protein 3(NLRP3),but the underlying molecular mechanisms remain incompletely understood.Inflammasomes are multi-protein complexes defined by a cytosolic innate immune sensor,usually a PRR,which recruits the adaptor molecule apoptosis-associated speck-like protein containing a caspase-recruitment domain(ASC)to activate the effector caspase-1 leading to the release of matured IL-1βand IL-18.Active caspase-1 further cleaves gasdermin D(GSDMD)allowing the N-terminal domain of GSDMD(GSDMD-N)to form pores in the plasma membrane,thus facilitating the release of matured IL-1βand IL-18.Pore-forming GSDMD-N further induces pyroptosis,an inflammatory form of cell death.