PtdIns4P on Dispersed Trans-Golgi Network Mediates NLRP3 Inflammasome Activation

The NLRP3 inflammasome, which has been linked to human inflammatory diseases, is activated by a plethora of stimuli. How NLRP3 is activated by such diverse stimuli is a central question that is unresolved. Here we show that different NLRP3 stimuli lead to a hitherto unknown disassembly of trans-Golgi network (TGN). NLRP3 is recruited to the dispersed TGN (dTGN) through ionic bonding between a conserved polybasic region in NLRP3 and the negatively-charged phosphatidylinositol 4-phosphate (PI4P) on dTGN. dTGN then serves as a scaffold for NLRP3 aggregation into multiple puncta, which polymerize the adaptor ASC to activate the downstream signaling cascade. Disruption of interaction between NLRP3 and PI4P on dTGN blocked NLRP3 aggregation and signaling. These results indicate that recruitment of NLRP3 to dTGN is an early and common cellular event that leads to NLRP3 aggregation and activation in response to diverse stimuli.