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

Nat Chem Biol. 2017 Jan;13(1):46-53. doi: 10.1038/nchembio.2229. Epub 2016 Nov 7.

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

Substances

  • 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