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

2016; Nature Portfolio; Volume: 13; Issue: 1 Linguagem: Inglês

10.1038/nchembio.2229

1552-4469

Marian C. Okondo, Darren C. Johnson, Ramya Sridharan, Eun Bin Go, Ashley J. Chui, Mitchell S. Wang, Sarah E. Poplawski, Wengen Wu, Yuxin Liu, Jack H. Lai, David G. Sanford, Michael O Arciprete, Todd R. Golub, William W. Bachovchin, Daniel A. Bachovchin,

Ubiquitin and proteasome pathways

Inhibitors of the post-proline-cleaving serine proteases DPP8 and DPP9 trigger a lytic form of programmed cell death called pyroptosis by activating pro-caspase-1 without autoproteolysis. 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.