15 years ago, the fundamental biology of an inflammatory signaling complex eventually dubbed "the
inflammasome" began to unravel in chronologic parallel with the discovery that many inflammatory diseases were associated with its hyperactivity. Though the genetic origins of
Familial Mediterranean Fever (FMF, caused my mutations in MEFV) were discovered first, it would take nearly two decades before the mechanistic connections to a
PYRIN inflammasome were made. In the interim, the intensive study of the NLRP3
inflammasome, and the diseases associated with its hyperactivation, have largely dictated the paradigm of
inflammasome composition and function. Despite impressive gains, focusing on NLRP3 left gaps in our understanding of
inflammasome biology. Foremost among these gaps were how
inflammasomes become activated and the connections between
inflammasome structure and function. Fortunately, work in another
inflammasome inducer, NLRC4, grew to fill those gaps. The current understanding of the NLRC4
inflammasome is perhaps the most comprehensive illustration of the
inflammasome paradigm: trigger (e.g. cytosolic
flagellin), sensor (NAIP), nucleator (NLRC4), adaptor (ASC), and effector (CASP1). Detailed work has also identified observations that challenge this paradigm. Simultaneously, the features unique to each
inflammasome offer a lesson in contrast, providing perspectives on
inflammasome activation, regulation, and function. In this review, we endeavor to highlight recent breakthroughs related to NLRC4
inflammasome structure and activation, important in vivo work in
infection and systemic
inflammation, and the characterization of a spectrum of human NLRC4-associated autoinflammatory diseases.