How location and cellular signaling combine to activate the NLRP3 inflammasome.
Abstract
NOD-, LRR-, and pyrin domain-containing 3 (NLRP3) is a cytosolic innate immune sensor of cellular stress signals, triggered by
infection and sterile inflammation. Upon detection of an activating stimulus, NLRP3 transitions from an inactive homo-oligomeric
multimer into an active multimeric inflammasome, which promotes the helical oligomeric assembly of the adaptor molecule ASC.
ASC oligomers provide a platform for caspase-1 activation, leading to the proteolytic cleavage and activation of proinflammatory
cytokines in the IL-1 family and gasdermin D, which can induce a lytic form of cell death. Recent studies investigating both the
cellular requirement for NLRP3 activation and the structure of NLRP3 have revealed the complex regulation of NLRP3 and the
multiple steps involved in its activation. This review presents a perspective on the biochemical and cellular processes controlling
the assembly of the NLRP3 inflammasome with particular emphasis on structural regulation and the role of organelles. We also
highlight the latest research on metabolic control of this inflammatory pathway and discuss promising clinical targets for
intervention.
Read more at Cell Mol Immunol (2022)