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.
Highlights
Cardiomyocyte death is increased in human heart failure and induction of cell death in experimental models is sufficient to cause heart failure.[5]
Depletion of GATA4 dose dependently induces cell death, a process that can be rescued by exogenous GATA4.6 Time course analysis of Dox effects revealed that the GATA4 protein was markedly depleted after 3 h of treatment
To confirm whether these changes occur at post-translational stages, a CMV-driven HA-GATA4 expression vector was transfected into the cardiomyocyte cell line HL-1 and treated with Dox
Summary
Cardiomyocyte death is increased in human heart failure and induction of cell death in experimental models is sufficient to cause heart failure.[5] Together, the data suggest that caspase-1 inactivates key molecules and pathways that promote cardiomyocyte survival. Transcription factor GATA4, a member of the zinc finger GATA family, has emerged as a key cardiomyocyte survival factor and an essential regulator of the postnatal cardiomyocyte stress response. Cardiomyocytes with downregulated GATA4 levels have increased rates of cell death at basal levels and in response to cardiotoxic drugs such as Doxorubicin (Dox) or tyrosine kinase inhibitors.[6,7] These cells fail to mount any adaptive response to mechanical or neuroendocrine stress.[8,9,10] GATA4 is a potent cardiogenic factor essential for cardiomyocyte commitment and differentiation.[11] We report that GATA4 is cleaved by caspase-1 in vitro and in cardiomyocytes. The data identify a target for caspase-1 in the nucleus and a pathway to explain its cardiac action
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