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

Nature chemical biology ·Vol. 13 ·No. 1 ·2017-01-00 ·Pages 46-53

Okondo MC, Johnson DC, Sridharan R, Go EB, Chui AJ, Wang MS, Poplawski SE, Wu W, Liu Y, Lai JH, Sanford DG, Arciprete MO, Golub TR, Bachovchin WW, Bachovchin DA

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.

MeSH Terms

Animals Boronic Acids/chemistry,pharmacology Caspase 1/deficiency,metabolism Cell Line Dipeptidases/antagonists & inhibitors,metabolism Dipeptides/chemistry,pharmacology Dipeptidyl-Peptidases and Tripeptidyl-Peptidases/antagonists & inhibitors,metabolism Dose-Response Relationship, Drug Humans Leukocytes, Mononuclear/drug effects,enzymology,pathology Macrophages/drug effects,enzymology,pathology Mice Molecular Conformation Pyroptosis/drug effects Serine Proteinase Inhibitors/chemistry,pharmacology Structure-Activity Relationship

Chemicals

Boronic Acids Dipeptides Serine Proteinase Inhibitors Dipeptidases DPP9 protein, human Dipeptidyl-Peptidases and Tripeptidyl-Peptidases DPP8 protein, human dipeptidyl peptidase 8, mouse dipeptidyl peptidase 9, mouse Caspase 1 talabostat

Authors & Affiliations

15 authors, click to expand affiliations / ORCID

Okondo Marian C

Chemical Biology Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA.

Johnson Darren C

Tri-Institutional PhD Program in Chemical Biology, Memorial Sloan Kettering Cancer Center, New York, New York, USA.

Sridharan Ramya

Graduate Program in Pharmacology, Weill Cornell Graduate School of Medical Sciences, New York, New York, USA.

Go Eun Bin

Tri-Institutional PhD Program in Chemical Biology, Memorial Sloan Kettering Cancer Center, New York, New York, USA.

Chui Ashley J

Tri-Institutional PhD Program in Chemical Biology, Memorial Sloan Kettering Cancer Center, New York, New York, USA.

Wang Mitchell S

Graduate Program in Pharmacology, Weill Cornell Graduate School of Medical Sciences, New York, New York, USA.

Poplawski Sarah E