title: Pyroptosis and Apoptosis Pathways Engage in Bidirectional Crosstalk in Monocytes and Macrophages.
abstract: Pyroptosis is a lytic form of programmed cell death mediated by the inflammatory caspase-1, -4, and -5. We recently discovered that small-molecule inhibitors of the serine peptidases DPP8 and DPP9 (DPP8/9) induce pro-caspase-1-dependent pyroptosis in monocytes and macrophages. Notably, DPP8/9 inhibitors, unlike microbial agents, absolutely require caspase-1 to induce cell death. Therefore, DPP8/9 inhibitors are useful probes to study caspase-1 in cells. Here, we show that, in the absence of the pyroptosis-mediating substrate gasdermin D (GSDMD), caspase-1 activates caspase-3 and -7 and induces apoptosis, demonstrating that GSDMD is the only caspase-1 substrate that induces pyroptosis. Conversely, we found that, during apoptosis, caspase-3/-7 specifically block pyroptosis by cleaving GSDMD at a distinct site from the inflammatory caspases that inactivates the protein. Overall, this work reveals bidirectional crosstalk between apoptosis and pyroptosis in monocytes and macrophages, further illuminating the complex interplay between cell death pathways in the innate immune system.
authors.affiliation: Chemical Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Cornelius Y
authors.initials: CY
authors.lastname: Taabazuing
authors.affiliation: Chemical Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Marian C
authors.initials: MC
authors.lastname: Okondo
authors.affiliation: Chemical Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Electronic address: bachovcd@mskcc.org.
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Bachovchin
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D020170:Caspase 1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D053179:Caspase 7 / Q000378:metabolism; D002460:Cell Line; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases / Q000037:antagonists & inhibitors / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D007113:Immunity, Innate; D047908:Intracellular Signaling Peptides and Proteins; D008070:Lipopolysaccharides / Q000633:toxicity; D008264:Macrophages / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D009000:Monocytes / Q000166:cytology / Q000378:metabolism*; D016297:Mutagenesis, Site-Directed; D009363:Neoplasm Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D009550:Nigericin / Q000633:toxicity; D028044:Phosphate-Binding Proteins; D000069292:Pyroptosis / Q000187:drug effects; D000067996:RAW 264.7 Cells; D000094524:Gasdermins
chemical_list: D020170:Caspase 1; D053148:Caspase 3; D053179:Caspase 7; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; D047908:Intracellular Signaling Peptides and Proteins; D008070:Lipopolysaccharides; D009363:Neoplasm Proteins; D009550:Nigericin; D028044:Phosphate-Binding Proteins; C498366:GSDMD protein, human; D000094524:Gasdermins
keywords: DPP8/9 inhibitors; apoptosis; caspase-1; caspase-3; caspase-7; cell death; gasdermin D; macrophages; monocytes; pyroptosis