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Cell Death Dis. 2014 Dec 11;5:e1566. doi: 10.1038/cddis.2014.524.

Caspase-1 cleavage of transcription factor GATA4 and regulation of cardiac cell fate.

Author information

1
Molecular Genetics and Cardiac Regeneration Laboratory, Departments of Biochemistry, Microbiology, and Immunology, University of Ottawa, 550 Cumberland, Room 246, Ottawa, Ontario K1N 6N5, Canada.
2
Departments of Medicine and Biochemistry, McGill University, 3648 Sir William Osler Promenade, Room 364, Montréal, Québec H3G 0B1, Canada.

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.

PMID:
25501827
PMCID:
PMC4649840
DOI:
10.1038/cddis.2014.524
[Indexed for MEDLINE]
Free PMC Article

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