DPP8 and DPP9 Inhibition Induces Pro-caspase-1-dependent Monocyte and Macrophage Pyroptosis

Overview

Journal Nat Chem Biol

Specialties Biochemistry
Biology
Chemistry

Date 2016 Nov 8

PMID 27820798

Citations 149

Authors

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

Soon will be listed here.

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.

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