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

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-1β and 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-1β and IL-18. Pore-forming GSDMD-N further induces pyroptosis, an inflammatory form of cell death.1 NLRP3 inflammasome activation typically entails NF-κB-driven transcriptional priming, which in turn licenses the cell for inflammasome assembly and activation.A previously discussed paradigm of rapid inflammasome assembly without the requirement for NF-κB-driven transcriptional priming involves simultaneous engagement of TLRs and NLRP3. While increasingly recognized, the molecular mechanisms and ensuing biological effects remain largely undefined. Recent work has demonstrated a role of IKKβ in activation of the NLRP3 inflammasome by recruiting NLRP3 to the dispersed trans-Golgi network. Given the activating effect of TLR signaling on IKK and the central role of NF-κB in inflammasome signaling, we scrutinized whether IKK could directly activate the inflammasome on top of its effects on priming.

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Proteomics

Projects: SyNergy - Published Datasets

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Created: 29th May 2024 at 11:28

Last updated: 15th Oct 2024 at 14:34

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