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Fig. 5 | Journal of Neuroinflammation

Fig. 5

From: Role of inflammasomes in multiple sclerosis and their potential as therapeutic targets

Fig. 5

Mechanism of NLRP1 and AIM2 activation. NLR family pyrin domain-containing protein 1 (NLRP1) has a unique function to find (FIIND) domain. The amino (N)-terminus inhibits the carboxy (C) terminus effector part of the protein, which contains the caspase-recruitment domain (CARD) domain, by a non-covalent interaction. A subsequent cleavage event of the N-terminus by a pathogenic trigger results in ubiquitination of the N-terminus inhibitory fragment by ubiquitin ligases, and the latter is degraded by the proteasome. The freed effector fragment induces apoptosis speck-like protein containing a CARD domain (ASC) speck formation, followed by caspase-1 activation and in turn processing of pro-IL-1β and IL-18 as well as cleavage of GasderminD (GSDMD). Secretion of the cytokines induces inflammation and GSDMD-induced pyroptosis. Absent in melanoma 2 (AIM2) inflammasome sensing of DNA triggers recruitment of the inflammasome adaptor ASC and caspase-1. Caspase-1 directly cleaves pro-IL-1β, pro-IL-18, and GSDMD. The amino (N)-terminus GSDMD-N fragment forms pores in the plasma membrane and initiates pyroptosis. IL-1β and IL-18 are released through the GSDMD pore leading to pyroptosis. GSDMD-C, carboxy-terminus GSDMD fragment

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