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

   

Authors:	Okondo, M. C.; Johnson, D. C.; Sridharan, R.; Go, E. B.; Chui, A. J.; Wang, M. S.; Poplawski, S. E.; Wu, W.; Liu, Y.; Lai, J. H.; Sanford, D. G.; Arciprete, M. O.; Golub, T. R.; Bachovchin, W. W.; Bachovchin, D. A.
Article Title:	DPP8 and DPP9 inhibition induces pro-caspase-1-dependent monocyte and macrophage pyroptosis
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. © 2016 The Author(s).
Journal Title:	Nature Chemical Biology
Volume:	13
Issue:	1
ISSN:	1552-4450
Publisher:	Nature Publishing Group
Date Published:	2017-01-01
Start Page:	46
End Page:	53
Language:	English
DOI:	10.1038/nchembio.2229
PROVIDER:	scopus
PUBMED:	27820798
PMCID:	PMC5477230
DOI/URL:	https://www.scopus.com/inward/record.uri?eid=2-s2.0-84994558912&doi=10.1038%2fnchembio.2229&partnerID=40&md5=3f6efd1e08cd8e463295faa181bc9215
Notes:	Article -- Export Date: 3 January 2017 -- Source: Scopus

https://synapse.mskcc.org/synapse/works/has_related_data_chk/103053