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Life Sci Alliance. 2020 Feb 12;3(3). pii: e202000664. doi: 10.26508/lsa.202000664. Print 2020 Mar.

Caspase-1 interdomain linker cleavage is required for pyroptosis.

Author information

1
Chemical Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
2
Weill Cornell/Rockefeller/Sloan Kettering Tri-Institutional MD-PhD Program, New York, NY, USA.
3
Tri-Institutional PhD Program in Chemical Biology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
4
Chemical Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA bachovcd@mskcc.org.
5
Pharmacology Program of the Weill Cornell Graduate School of Medical Sciences, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Abstract

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.

PMID:
32051255
DOI:
10.26508/lsa.202000664
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