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Caspase-1 interdomain linker cleavage is required for pyroptosis

Daniel P Ball, Cornelius Y Taabazuing, Andrew R Griswold, Elizabeth L Orth, Sahana D Rao, Ilana B Kotliar, Lauren E Vostal, Darren C Johnson, View ORCID ProfileDaniel A Bachovchin  Correspondence email
Daniel P Ball
1Chemical Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA
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Cornelius Y Taabazuing
1Chemical Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA
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Andrew R Griswold
2Weill Cornell/Rockefeller/Sloan Kettering Tri-Institutional MD-PhD Program, New York, NY, USA
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Elizabeth L Orth
3Tri-Institutional PhD Program in Chemical Biology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
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Sahana D Rao
3Tri-Institutional PhD Program in Chemical Biology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
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Ilana B Kotliar
3Tri-Institutional PhD Program in Chemical Biology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
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Lauren E Vostal
3Tri-Institutional PhD Program in Chemical Biology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
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Darren C Johnson
3Tri-Institutional PhD Program in Chemical Biology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
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Daniel A Bachovchin
1Chemical Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA
3Tri-Institutional PhD Program in Chemical Biology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
4Pharmacology Program of the Weill Cornell Graduate School of Medical Sciences, Memorial Sloan Kettering Cancer Center, New York, NY, USA
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  • ORCID record for Daniel A Bachovchin
  • For correspondence: bachovcd@mskcc.org
Published 12 February 2020. DOI: 10.26508/lsa.202000664
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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.

  • Received January 31, 2020.
  • Revision received February 3, 2020.
  • Accepted February 4, 2020.
  • © 2020 Ball et al.
Creative Commons logoCreative Commons logohttps://creativecommons.org/licenses/by/4.0/

This article is available under a Creative Commons License (Attribution 4.0 International, as described at https://creativecommons.org/licenses/by/4.0/).

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Caspase-1 activation requires autoproteolysis
Daniel P Ball, Cornelius Y Taabazuing, Andrew R Griswold, Elizabeth L Orth, Sahana D Rao, Ilana B Kotliar, Lauren E Vostal, Darren C Johnson, Daniel A Bachovchin
Life Science Alliance Feb 2020, 3 (3) e202000664; DOI: 10.26508/lsa.202000664

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Caspase-1 activation requires autoproteolysis
Daniel P Ball, Cornelius Y Taabazuing, Andrew R Griswold, Elizabeth L Orth, Sahana D Rao, Ilana B Kotliar, Lauren E Vostal, Darren C Johnson, Daniel A Bachovchin
Life Science Alliance Feb 2020, 3 (3) e202000664; DOI: 10.26508/lsa.202000664
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Volume 3, No. 3
March 2020
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