期刊
NATURE CHEMICAL BIOLOGY
卷 13, 期 1, 页码 46-53出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/NCHEMBIO.2229
关键词
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资金
- Josie Robertson Foundation
- MSKCC Core Grant [P30 CA008748]
- NCI [U54CA112962]
- HHMI
- NIH [CA174008-01A1, NIH NIGMS T32 GM115327-Tan]
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-113 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.
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