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Cell Chem Biol. 2018 Mar 15;25(3):262-267.e5. doi: 10.1016/j.chembiol.2017.12.013. Epub 2018 Jan 27.

Inhibition of Dpp8/9 Activates the Nlrp1b Inflammasome.

Author information

1
Chemical Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
2
Tri-institutional PhD Program in Chemical Biology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
3
Department of Developmental, Chemical, & Molecular Biology, Tufts University Sackler School of Graduate Biomedical Sciences, Boston, MA 02111, USA.
4
Chemical Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Tri-institutional PhD Program in Chemical Biology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Electronic address: bachovcd@mskcc.org.

Abstract

Val-boroPro (PT-100, Talabostat) induces powerful anti-tumor immune responses in syngeneic cancer models, but its mechanism of action has not yet been established. Val-boroPro is a non-selective inhibitor of post-proline-cleaving serine proteases, and the inhibition of the highly related cytosolic serine proteases Dpp8 and Dpp9 (Dpp8/9) by Val-boroPro was recently demonstrated to trigger an immunostimulatory form of programmed cell death known as pyroptosis selectively in monocytes and macrophages. Here we show that Dpp8/9 inhibition activates the inflammasome sensor protein Nlrp1b, which in turn activates pro-caspase-1 to mediate pyroptosis. This work reveals a previously unrecognized mechanism for activating an innate immune pattern recognition receptor and suggests that Dpp8/9 serve as an intracellular checkpoint to restrain Nlrp1b and the innate immune system.

KEYWORDS:

Dpp8/9; Nlrp1b inflammasome; Val-boroPro; caspase-1; pyroptosis

PMID:
29396289
PMCID:
PMC5856610
[Available on 2019-03-15]
DOI:
10.1016/j.chembiol.2017.12.013

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