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, Affiliations Contributions Corresponding author, Nature Chemical Biology 13, 46-53 (2017) doi:10.1038/nchembio.2229, Received 13 May 2016 Accepted 30 August 2016 Published online 07 November 2016.
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-1? 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.
Source: nature research Journal