Fig. 4.

Redox regulation of NLRP3.

ROS modulate the NLRP3 inflammasome, a protein complex that mediates IL-1β processing and secretion. ROS enhance NIMA-related kinase 7 (NEK7) phosphorylation and its interaction with NLRP3 through a poorly defined mechanism. Additionally, deglutathionylation of Cys253 on NEK7 is important for its interaction with NLRP3 (1). Itaconate derivatives targets Cys548 of the NLRP3 inflammasome to prevent its interaction with NEK7 (2). ROS oxidize Cys192 of GSDMD to enhance its pore-forming activity (3) while palmitoylation of Cys192 of GSDMD leads to membrane translocation of GSDMD and the subsequent pore-formation and pyroptosis. Furthermore, ROS promote cleavage of GSDMD, mobilization to the plasma membrane, oligomerization and eventually pore formation. GSDMD is also regulated by succination and alkylation by itaconate.