RT Journal Article SR Electronic T1 Human caspase-1 autoproteolysis is required for ASC-dependent and -independent inflammasome activation JF bioRxiv FD Cold Spring Harbor Laboratory SP 681304 DO 10.1101/681304 A1 Daniel P. Ball A1 Cornelius Y. Taabazuing A1 Andrew R. Griswold A1 Elizabeth L. Orth A1 Sahana D. Rao A1 Ilana B. Kotliar A1 Darren C. Johnson A1 Daniel A. Bachovchin YR 2019 UL http://biorxiv.org/content/early/2019/06/24/681304.abstract AB Pathogen-related signals induce a number of cytosolic pattern-recognition receptors (PRRs) to form canonical inflammasomes, which activate pro-caspase-1 and trigger pyroptotic cell death. All well-studied PRRs oligomerize with the pro-caspase-1-adapter protein ASC to generate a single large structure in the cytosol, which induces the autoproteolysis and activation of the pro-caspase-1 zymogen. However, several PRRs can also directly interact with pro-caspase-1 without ASC, forming much smaller “ASC-independent” inflammasomes. It is currently thought that pro-caspase-1 autoproteolysis does not occur during, and is not required for, ASC-independent inflammasome activation. Here, we show that the related human PRRs NLRP1 and CARD8 exclusively form ASC-dependent and ASC-independent inflammasomes, respectively, identifying CARD8 as the first PRR that cannot form an ASC-containing signaling platform. Despite their different structures, we discovered that both the NLRP1 and CARD8 inflammasomes require pro-caspase-1 autoproteolysis between the small and large catalytic subunits to induce pyroptosis. Thus, pro-caspase-1 self-cleavage is an obligate regulatory step in the activation of human canonical inflammasomes.