دورية أكاديمية
DPP8 and DPP9 inhibition induces pro-caspase-1-dependent monocyte and macrophage pyroptosis.
| العنوان: | DPP8 and DPP9 inhibition induces pro-caspase-1-dependent monocyte and macrophage pyroptosis. |
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| المؤلفون: | Okondo MC; Chemical Biology Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA., Johnson DC; Tri-Institutional PhD Program in Chemical Biology, Memorial Sloan Kettering Cancer Center, New York, New York, USA., Sridharan R; Graduate Program in Pharmacology, Weill Cornell Graduate School of Medical Sciences, New York, New York, USA., Go EB; Tri-Institutional PhD Program in Chemical Biology, Memorial Sloan Kettering Cancer Center, New York, New York, USA., Chui AJ; Tri-Institutional PhD Program in Chemical Biology, Memorial Sloan Kettering Cancer Center, New York, New York, USA., Wang MS; Graduate Program in Pharmacology, Weill Cornell Graduate School of Medical Sciences, New York, New York, USA., Poplawski SE; Department of Developmental, Chemical &Molecular Biology, Sackler School of Graduate Biomedical Sciences, Tufts University, Boston, Massachusetts, USA., Wu W; Department of Developmental, Chemical &Molecular Biology, Sackler School of Graduate Biomedical Sciences, Tufts University, Boston, Massachusetts, USA., Liu Y; Department of Developmental, Chemical &Molecular Biology, Sackler School of Graduate Biomedical Sciences, Tufts University, Boston, Massachusetts, USA., Lai JH; Department of Developmental, Chemical &Molecular Biology, Sackler School of Graduate Biomedical Sciences, Tufts University, Boston, Massachusetts, USA., Sanford DG; Department of Developmental, Chemical &Molecular Biology, Sackler School of Graduate Biomedical Sciences, Tufts University, Boston, Massachusetts, USA., Arciprete MO; Department of Developmental, Chemical &Molecular Biology, Sackler School of Graduate Biomedical Sciences, Tufts University, Boston, Massachusetts, USA., Golub TR; 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., Bachovchin WW; Department of Developmental, Chemical &Molecular Biology, Sackler School of Graduate Biomedical Sciences, Tufts University, Boston, Massachusetts, USA.; Arisaph Pharmaceuticals, Boston, Massachusetts, USA., Bachovchin DA; 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. |
| المصدر: | Nature chemical biology [Nat Chem Biol] 2017 Jan; Vol. 13 (1), pp. 46-53. Date of Electronic Publication: 2016 Nov 07. |
| نوع المنشور: | Journal Article |
| اللغة: | English |
| بيانات الدورية: | Publisher: Nature Pub. Group Country of Publication: United States NLM ID: 101231976 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1552-4469 (Electronic) Linking ISSN: 15524450 NLM ISO Abbreviation: Nat Chem Biol Subsets: MEDLINE |
| أسماء مطبوعة: | Original Publication: New York, NY : Nature Pub. Group, [2005]- |
| مواضيع طبية MeSH: | Boronic Acids/*pharmacology , Caspase 1/*metabolism , Dipeptidases/*antagonists & inhibitors , Dipeptides/*pharmacology , Dipeptidyl-Peptidases and Tripeptidyl-Peptidases/*antagonists & inhibitors , Leukocytes, Mononuclear/*drug effects , Macrophages/*drug effects , Pyroptosis/*drug effects , Serine Proteinase Inhibitors/*pharmacology, Animals ; Boronic Acids/chemistry ; Caspase 1/deficiency ; Cell Line ; Dipeptidases/metabolism ; Dipeptides/chemistry ; Dipeptidyl-Peptidases and Tripeptidyl-Peptidases/metabolism ; Dose-Response Relationship, Drug ; Humans ; Leukocytes, Mononuclear/enzymology ; Leukocytes, Mononuclear/pathology ; Macrophages/enzymology ; Macrophages/pathology ; Mice ; Molecular Conformation ; Serine Proteinase Inhibitors/chemistry ; Structure-Activity Relationship |
| مستخلص: | 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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| معلومات مُعتمدة: | R41 CA174008 United States CA NCI NIH HHS; T32 CA062948 United States CA NCI NIH HHS; T32 GM115327 United States GM NIGMS NIH HHS; P30 CA008748 United States CA NCI NIH HHS; R01 CA163930 United States CA NCI NIH HHS; U54 CA112962 United States CA NCI NIH HHS |
| المشرفين على المادة: | 0 (Boronic Acids) 0 (Dipeptides) 0 (Serine Proteinase Inhibitors) EC 3.4.13.- (Dipeptidases) EC 3.4.14.- (DPP9 protein, human) EC 3.4.14.- (Dipeptidyl-Peptidases and Tripeptidyl-Peptidases) EC 3.4.14.5 (DPP8 protein, human) EC 3.4.14.5 (dipeptidyl peptidase 8, mouse) EC 3.4.14.5 (dipeptidyl peptidase 9, mouse) EC 3.4.22.36 (Caspase 1) KZ1O2SH88Z (talabostat) |
| تواريخ الأحداث: | Date Created: 20161108 Date Completed: 20170515 Latest Revision: 20210617 |
| رمز التحديث: | 20231215 |
| مُعرف محوري في PubMed: | PMC5477230 |
| DOI: | 10.1038/nchembio.2229 |
| PMID: | 27820798 |
| قاعدة البيانات: | MEDLINE |
Find this article in full text from Springer Verlag. 
Full Text Finder | تدمد: | 1552-4469 |
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| DOI: | 10.1038/nchembio.2229 |