P2X7 mediates loss of intracellular K+ ATP binds to P2X7 P2X7 forms oligomeric non-selective cation channels ASC is recruited via a PYD-PYD interaction Pyrin binds ASC The CARD domain of ASC recruits Procaspase-1 PSTPIP1 binds Pyrin P2X7 mediates membrane pores that include pannexin-1 SGT1 binds HSP90 SGT1:HSP90 binds inactive NLRP3 TXNIP binds reduced thioredoxin ROS oxidize thioredoxin TXNIP is released from oxidized thioredoxin TXNIP binds NLRP3 NLRP3 activation by small molecules NLRP3 activation by elicitor proteins NLRP3 oligomerizes via NACHT domains PathwayStep6898 PathwayStep6889 PathwayStep6887 PathwayStep6888 PathwayStep6893 PathwayStep6892 PathwayStep6891 PathwayStep6890 PathwayStep6897 PathwayStep6896 PathwayStep6895 PathwayStep6894 PathwayStep6883 PathwayStep6884 PathwayStep6885 PathwayStep6886 PathwayStep6882 The NLRP3 inflammasome Authored: Jupe, S, 2010-04-22 Edited: Jupe, S, 2011-04-28 Pubmed11607846 Pubmed12766759 Pubmed15075209 Pubmed16498449 Pubmed17036048 Pubmed18604214 Pubmed19501527 Pubmed20303873 Reactome Database ID Release 43844456 Reactome, http://www.reactome.org ReactomeREACT_75808 Reviewed: Kufer, TA, 2011-04-28 Reviewed: Rittinger, K, 2011-06-06 Reviewed: Wong, Edmond, 2011-06-06 The NLRP3 (Cryopyrin) inflammasome is currently the best characterized. It consists of NLRP3, ASC (PYCARD) and procaspase-1; CARD8 (Cardinal) is also suggested to be a component. It is activated by a number of pathogens and bacterial toxins as well as diverse PAMPs, danger-associated molecular patterns (DAMPS) such as hyaluronan and uric acid, and exogenous irritants such as silica and asbestos (see Table S1 Schroder & Tschopp, 2010).<br> Mutations in NLRP3 which lead to constitutive activation are linked to the human diseases Muckle-Wells syndrome, familial cold autoinflammatory syndrome and NOMID (Ting et al. 2006), characterized by skin rashes and other symptoms associated with generalized inflammation. The cause of these symptoms is uncontrolled IL-1 beta production. Multiple studies have shown that activation of the NLRP3 inflammasome by particulate activators (e.g. Hornung et al. 2008) requires phagocytosis, but this is not required for the response to ATP, which is mediated by the P2X7 receptor (Kahlenberg & Dubyak, 2004) and appears to involve the pannexin membrane channel (Pellegrin & Suprenenant 2006). Direct binding of activators to NLRP3 has not been demonstrated and the exact process of activation is unclear, though it is speculated to involve changes in conformation that free the NACHT domain for oligomerization (Inohara & Nunez 2001, 2003).