DPP8 and DPP9 inhibition induces pro-caspase-1-dependent monocyte and macrophage pyroptosis.
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.
Chemical Biology Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
Marian C
MC
Okondo
Tri-Institutional PhD Program in Chemical Biology, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
Darren C
DC
Johnson
Graduate Program in Pharmacology, Weill Cornell Graduate School of Medical Sciences, New York, New York, USA.
Ramya
R
Sridharan
Tri-Institutional PhD Program in Chemical Biology, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
Eun Bin
EB
Go
Tri-Institutional PhD Program in Chemical Biology, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
Ashley J
AJ
Chui
Graduate Program in Pharmacology, Weill Cornell Graduate School of Medical Sciences, New York, New York, USA.
Mitchell S
MS
Wang
Department of Developmental, Chemical &Molecular Biology, Sackler School of Graduate Biomedical Sciences, Tufts University, Boston, Massachusetts, USA.
Sarah E
SE
Poplawski
Department of Developmental, Chemical &Molecular Biology, Sackler School of Graduate Biomedical Sciences, Tufts University, Boston, Massachusetts, USA.
Wengen
W
Wu
Department of Developmental, Chemical &Molecular Biology, Sackler School of Graduate Biomedical Sciences, Tufts University, Boston, Massachusetts, USA.
Yuxin
Y
Liu
Department of Developmental, Chemical &Molecular Biology, Sackler School of Graduate Biomedical Sciences, Tufts University, Boston, Massachusetts, USA.
Jack H
JH
Lai
Department of Developmental, Chemical &Molecular Biology, Sackler School of Graduate Biomedical Sciences, Tufts University, Boston, Massachusetts, USA.
David G
DG
Sanford
Department of Developmental, Chemical &Molecular Biology, Sackler School of Graduate Biomedical Sciences, Tufts University, Boston, Massachusetts, USA.
Michael O
MO
Arciprete
The Eli and Edythe L. Broad Institute, Cambridge, Massachusetts, USA.|Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.|Harvard Medical School, Boston, Massachusetts, USA.|Howard Hughes Medical Institute, Chevy Chase, Maryland, USA.
Todd R
TR
Golub
Department of Developmental, Chemical &Molecular Biology, Sackler School of Graduate Biomedical Sciences, Tufts University, Boston, Massachusetts, USA.|Arisaph Pharmaceuticals, Boston, Massachusetts, USA.
William W
WW
Bachovchin
Chemical Biology Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA.|Tri-Institutional PhD Program in Chemical Biology, Memorial Sloan Kettering Cancer Center, New York, New York, USA.|Graduate Program in Pharmacology, Weill Cornell Graduate School of Medical Sciences, New York, New York, USA.
Daniel A
DA
Bachovchin
D000818:Animals; D001897:Boronic Acids / Q000737:chemistry / Q000494:pharmacology*; D020170:Caspase 1 / Q000172:deficiency / Q000378:metabolism*; D002460:Cell Line; D004150:Dipeptidases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004151:Dipeptides / Q000737:chemistry / Q000494:pharmacology*; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D008264:Macrophages / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D051379:Mice; D008968:Molecular Conformation; D000069292:Pyroptosis / Q000187:drug effects*; D015842:Serine Proteinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D001897:Boronic Acids; D004151:Dipeptides; D015842:Serine Proteinase Inhibitors; D004150:Dipeptidases; C471241:DPP9 protein, human; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; C487997:DPP8 protein, human; C585325:dipeptidyl peptidase 8, mouse; C585326:dipeptidyl peptidase 9, mouse; D020170:Caspase 1; C514044:talabostat