title: Caspase-1 cleavage of transcription factor GATA4 and regulation of cardiac cell fate.
abstract: Caspase-1 or interleukin-1β (IL-1β) converting enzyme is a pro-inflammatory member of the caspase family. An IL-1β-independent role for caspase-1 in cardiomyocyte cell death and heart failure has emerged but the mechanisms underlying these effects are incompletely understood. Here, we report that transcription factor GATA4, a key regulator of cardiomyocyte survival and adaptive stress response is an in vivo and in vitro substrate for caspase-1. Caspase-1 mediated cleavage of GATA4 generates a truncated protein that retains the ability to bind DNA but lacks transcriptional activation domains and acts as a dominant negative regulator of GATA4. We show that caspase-1 is rapidly activated in cardiomyocyte nuclei treated with the cell death inducing drug Doxorubicin. We also find that inhibition of caspase-1 alone is as effective as complete caspase inhibition at rescuing GATA4 degradation and myocyte cell death. Caspase-1 inhibition of GATA4 transcriptional activity is rescued by HSP70, which binds directly to GATA4 and masks the caspase recognition motif. The data identify a caspase-1 nuclear substrate and suggest a direct role for caspase-1 in transcriptional regulation. This mechanism may underlie the inflammation-independent action of caspase-1 in other organs.
authors.affiliation: Molecular Genetics and Cardiac Regeneration Laboratory, Departments of Biochemistry, Microbiology, and Immunology, University of Ottawa, 550 Cumberland, Room 246, Ottawa, Ontario K1N 6N5, Canada.
authors.forename: A
authors.initials: A
authors.lastname: Aries
authors.affiliation: Molecular Genetics and Cardiac Regeneration Laboratory, Departments of Biochemistry, Microbiology, and Immunology, University of Ottawa, 550 Cumberland, Room 246, Ottawa, Ontario K1N 6N5, Canada.
authors.forename: J
authors.initials: J
authors.lastname: Whitcomb
authors.affiliation: Departments of Medicine and Biochemistry, McGill University, 3648 Sir William Osler Promenade, Room 364, Montréal, Québec H3G 0B1, Canada.
authors.forename: W
authors.initials: W
authors.lastname: Shao
authors.affiliation: Molecular Genetics and Cardiac Regeneration Laboratory, Departments of Biochemistry, Microbiology, and Immunology, University of Ottawa, 550 Cumberland, Room 246, Ottawa, Ontario K1N 6N5, Canada.
authors.forename: H
authors.initials: H
authors.lastname: Komati
authors.affiliation: Departments of Medicine and Biochemistry, McGill University, 3648 Sir William Osler Promenade, Room 364, Montréal, Québec H3G 0B1, Canada.
authors.forename: M
authors.initials: M
authors.lastname: Saleh
authors.affiliation: Molecular Genetics and Cardiac Regeneration Laboratory, Departments of Biochemistry, Microbiology, and Immunology, University of Ottawa, 550 Cumberland, Room 246, Ottawa, Ontario K1N 6N5, Canada.
authors.forename: M
authors.initials: M
authors.lastname: Nemer
mesh_terms: D000818:Animals; D020170:Caspase 1 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D002467:Cell Nucleus / Q000201:enzymology / Q000235:genetics / Q000378:metabolism; D002470:Cell Survival; D002478:Cells, Cultured; D050991:GATA4 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D050884:HSP72 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D032383:Myocytes, Cardiac / Q000166:cytology / Q000201:enzymology* / Q000378:metabolism; D011485:Protein Binding; D011499:Protein Processing, Post-Translational; D017434:Protein Structure, Tertiary; D051381:Rats; D017207:Rats, Sprague-Dawley; D015533:Transcriptional Activation
chemical_list: D050991:GATA4 Transcription Factor; D050884:HSP72 Heat-Shock Proteins; D020170:Caspase 1