The NLRP1 and CARD8 inflammasomes

The term inflammasome was first coined in 2002 by Martinon et al. to describe a protein complex formed between NLRP1, ASC, and caspase-1 (CASP1) that acted in concert to promote CASP1 activation and the processing of the inflammatory cytokine pro-IL-1β into the active p17 isoform [1]. While human NLRP1 was the first inflammasome identified, its role in host defense and molecular mechanisms of activation remained elusive for nearly 20 years. Recent work has shed light on this unusual inflammasome, uncovering the function of NLRP1 as a sensor of its own stability. Cellular stresses or pathogen-associated activities that drive the proteasomal degradation of NLRP1 lead to the liberation of an autoinhibited C-terminal fragment that assembles to form the active inflammasome. In this way, NLRP1 is able to recognize and respond to a broad range of disruptions in cellular homeostasis and/or the enzymatic activities of pathogen-secreted effectors. This chapter will cover the biochemical details underlying the mechanisms of activation of the NLRP1 and related CARD8 inflammasomes and their roles in host defense against pathogens.