Deubiquitinase BRISC promotes pyroptosis induced by the NLRP3 inflammasome.
Assembly of the NLRP3 inflammasome is triggered by a range of cellular insults. BRISC interacts with NLRP3 in complex with NEK7 and removes K63-linked polyubiquitin from NLRP3. Deubiquitination of NLRP3 is required for NLRP3 to interact with ASC, the adaptor for caspase-1. Activation of caspase-1 within the NLRP3-nucleated complex results in cleavage of its substrates pro-IL-1β and pro-IL-18, yielding the biologically active cytokines. Caspase-1 also cleaves GSDMD, producing an N-terminal fragment that assembles oligomeric pores in the plasma membrane capable of releasing IL-1β and IL-18. GSDMD pores also disrupt the electrochemical gradient and kill the cell. Pyroptosis culminates in large scale rupture of the plasma membrane, which is mediated by the membrane protein NINJ1. Precisely how NINJ1 triggers membrane breakdown and the release larger intracellular proteins such as lactate dehydrogenase (LDH) is unclear. Other proteases that can elicit the pore-forming fragment of GSDMD include human caspase-4 (mouse counterpart caspase-11) and caspase-5, which are activated by cytosolic lipopolysaccharide (LPS). Figure created with BioRender.com.