Send to

Choose Destination
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

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


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.

[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center