| First Author | Aries A | Year | 2014 |
| Journal | Cell Death Dis | Volume | 5 |
| Pages | e1566 | PubMed ID | 25501827 |
| Mgi Jnum | J:318268 | Mgi Id | MGI:6858991 |
| Doi | 10.1038/cddis.2014.524 | Citation | Aries A, et al. (2014) Caspase-1 cleavage of transcription factor GATA4 and regulation of cardiac cell fate. Cell Death Dis 5:e1566 |
| abstractText | Caspase-1 or interleukin-1beta (IL-1beta) converting enzyme is a pro-inflammatory member of the caspase family. An IL-1beta-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. |
