TY - JOUR T1 - Caspase-1 interdomain linker cleavage is required for pyroptosis JF - Life Science Alliance JO - Life Sci. Alliance DO - 10.26508/lsa.202000664 VL - 3 IS - 3 SP - e202000664 AU - Daniel P Ball AU - Cornelius Y Taabazuing AU - Andrew R Griswold AU - Elizabeth L Orth AU - Sahana D Rao AU - Ilana B Kotliar AU - Lauren E Vostal AU - Darren C Johnson AU - Daniel A Bachovchin Y1 - 2020/03/01 UR - https://www.life-science-alliance.org/content/3/3/e202000664.abstract N2 - 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 inflammasome-forming PRRs oligomerize with the adapter protein ASC (apoptosis-associated speck-like protein containing a CARD) to generate a large structure in the cytosol, which induces the dimerization, autoproteolysis, and activation of the pro-caspase-1 zymogen. However, several PRRs can also directly interact with pro-caspase-1 without ASC, forming smaller “ASC-independent” inflammasomes. It is currently thought that little, if any, pro-caspase-1 autoproteolysis occurs during, and is not required for, ASC-independent inflammasome signaling. 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 canonical inflammasome-forming PRR that does not 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 a required regulatory step for pyroptosis induced by human canonical inflammasomes. ER -