Phafin2 modulates the aggregation of NLRP3 on dispersed trans-Golgi network

NLRP3 is one of the central players in innate immune signaling. Upon stimulation, NLRP3 could oligomerize and recruit ASC, NEK7, and caspase 1 (CASP1), then assemble into inflammasome, triggering downstream inflammation and pyroptosis. Recently, it was reported that both potassium efflux dependent and independent signaling, could lead to the formation of dispersed TGN (dTGN), where NLRP3 was initially recruited. Interestingly, the phosphatidylinositol-4-phosphate (PI4P) enriched on dTGN is indispensable for NLRP3 recruitment. In this study, we found that Phafin2, which can bind PI4P and PI3P via its PH and FYVE domains respectively, could modulate the NLRP3 aggregation on dTGN, thus regulating the cell pyroptosis. Phafin2 affects NLRP3 aggregation indirectly by influencing the constitution of dTGN. Our study unravels Phafin2 might act as a critical regulator of NLRP3-mediated pyroptosis, thus providing a new therapeutic target for human diseases associated with NLRP3-involved inflammation.