Fig. 3.

Diagram of signaling in a cardiomyocyte showing how SUMO modification differentially controls extra-nuclear and nuclear events, which can be coordinately regulated by the shuttling of SENPs between these two compartments. In the cytoplasm, up-regulation of SUMO modification on SERCA2a, NEMO, LKB1, and AMPKs up-regulates their functions, while SUMOylation of PKCa and DRP1 inhibits PKCa kinase activation and DRP1 function for inducing mitochondrial fragmentation. In the nucleus SUMOylation of proteins in the tissue factor complex including XBP-1s, ERK5, and PPARs inhibits their transcriptional activity. ERK5 SUMOylation inhibits ERK5-mediated ICER reduction by inhibiting CHIP E3 ligase activity, which can also inhibit TFs activity. SUMOylation of HDACs can augment their function, leading to accelerated inhibition of transcription. These data suggest that SUMOylation events in the extra-nuclear compartments in cardiomyocytes are cardio-protective, while the nuclear SUMOylation events are detrimental to these cells. We propose the shuttling of SENPs between the two compartments plays an important role in the response to various forms of cardiac insults and decides the fate of the cardiomyocytes.