Mechanistic Elucidation of Inflammasome Assembly and Regulation

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Abstract Inflammasomes are supramolecular signaling complexes that activate a subset of caspases known as inflammatory caspases such as caspase-1. Upon stimulation by microbial and damage-associated signals, inflammasomes assemble to elicit the first line of host defense by proteolytic maturation of cytokines IL-1β and IL-18, and by induction of pyroptotic cell death. Assembly of an inflammasome requires activation of an upstream sensor, a downstream effector, and in most cases an adaptor molecule such as apoptosis-associate speck-like protein containing a caspase recruitment domain (ASC). Depending on whether ASC is required, inflammasomes can be categorized into ASC-dependent and ASC-independent inflammasomes. Despite the biological importance of inflammasomes in innate immunity, no structural and mechanistic information is available. In this application, we propose structural, biochemical, biophysical and cell biological studies on AIM2, NLRP3 and NAIP inflammasomes, which are representative members of ASC-dependent and ASC-independent inflammasomes. The key structural scaffolds for the assembly of these inflammasomes are composed of filaments of Pyrin domains (PYD) and caspase recruitment domains (CARD), and polymerized disk-like structures by nucleotide-binding domains (NBD). Inflammasomes have been implicated in many human diseases. Most notably, failure to curb the activity of inflammasomes is linked to autoinflammatory conditions such as familial Mediterranean fever and NLRP3-associated periodic syndromes including familial cold autoinflammatory syndrome, Muckle-Wells syndrome, and chronic infantile neurological cutaneous and articular syndrome–neonatal onset multisystem inflammatory disease. As predisposing factors, inflammasome component proteins have been associated with many inflammatory diseases such as psoriasis, lupus, and inflammatory bowel diseases such as ulcerative colitis and Crohn's diseases.