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Nat Chem Biol. 2017 Jan;13(1):46-53. doi: 10.1038/nchembio.2229. Epub 2016 Nov 7.

DPP8 and DPP9 inhibition induces pro-caspase-1-dependent monocyte and macrophage pyroptosis.

Author information

1
Chemical Biology Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
2
Tri-Institutional PhD Program in Chemical Biology, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
3
Graduate Program in Pharmacology, Weill Cornell Graduate School of Medical Sciences, New York, New York, USA.
4
Department of Developmental, Chemical &Molecular Biology, Sackler School of Graduate Biomedical Sciences, Tufts University, Boston, Massachusetts, USA.
5
The Eli and Edythe L. Broad Institute, Cambridge, Massachusetts, USA.
6
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
7
Harvard Medical School, Boston, Massachusetts, USA.
8
Howard Hughes Medical Institute, Chevy Chase, Maryland, USA.
9
Arisaph Pharmaceuticals, Boston, Massachusetts, USA.

Abstract

Val-boroPro (Talabostat, PT-100), a nonselective inhibitor of post-proline cleaving serine proteases, stimulates mammalian immune systems through an unknown mechanism of action. Despite this lack of mechanistic understanding, Val-boroPro has attracted substantial interest as a potential anticancer agent, reaching phase 3 trials in humans. Here we show that Val-boroPro stimulates the immune system by triggering a proinflammatory form of cell death in monocytes and macrophages known as pyroptosis. We demonstrate that the inhibition of two serine proteases, DPP8 and DPP9, activates the pro-protein form of caspase-1 independent of the inflammasome adaptor ASC. Activated pro-caspase-1 does not efficiently process itself or IL-1β but does cleave and activate gasdermin D to induce pyroptosis. Mice lacking caspase-1 do not show immune stimulation after treatment with Val-boroPro. Our data identify what is to our knowledge the first small molecule that induces pyroptosis and reveals a new checkpoint that controls the activation of the innate immune system.

PMID:
27820798
PMCID:
PMC5477230
DOI:
10.1038/nchembio.2229
[Indexed for MEDLINE]
Free PMC Article

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