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bioRxiv · 10.1101/681304

Human caspase-1 autoproteolysis is required for ASC-dependent and -independent inflammasome activation

Ball, D. P.·Taabazuing, C. Y.·Griswold, A. R.·Orth, E. L.·Rao, S. D.·Kotliar, I. B.·Johnson, D. C.·Bachovchin, D. A.
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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 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.

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Ball, D. P., Taabazuing, C. Y., Griswold, A. R., Orth, E. L., Rao, S. D., Kotliar, I. B., Johnson, D. C., Bachovchin, D. A.. 2019-06-24. Human caspase-1 autoproteolysis is required for ASC-dependent and -independent inflammasome activation. https://doi.org/10.1101/681304

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