Caspase-1 interdomain linker cleavage is required for pyroptosis

• Published in: Life science alliance Vol. 3; no. 3; p. e202000664
• Main Authors: Ball, Daniel P, Taabazuing, Cornelius Y, Griswold, Andrew R, Orth, Elizabeth L, Rao, Sahana D, Kotliar, Ilana B, Vostal, Lauren E, Johnson, Darren C, Bachovchin, Daniel A
• Format: Journal Article
• Language: English
• Published: United States Life Science Alliance LLC 01.03.2020
• Subjects: Adaptor Proteins, Signal Transducing - metabolism; Apoptosis; Apoptosis Regulatory Proteins - metabolism; CARD Signaling Adaptor Proteins - metabolism; Carrier Proteins - metabolism; Caspase 1 - metabolism; HEK293 Cells; Humans; Inflammasomes - metabolism; NLR Family, Pyrin Domain-Containing 3 Protein - metabolism; Pyroptosis - physiology; Signal Transduction; THP-1 Cells
• ISSN: 2575-1077; 2575-1077
• DOI: 10.26508/lsa.202000664

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.