Nuclear Localization of Endothelin-Converting Enzyme-1: Subisoform Specificity

Objective-The biosynthesis of endothelin-1 (ET-1), the most potent vasoconstrictor with mitogenic properties, involves the processing of intermediate protein big ET-1 by a unique metalloprotease, endothelin-converting enzyme-1 (ECE-1), ECE-1 has 4 subisoforms that possess the same catalytic properties but different localization patterns on the plasma membrane and cytosol. We investigated the trafficking of ECE-1 subisoforms using green fluorescent protein-tagged recombinant enzymes in target and nontarget cells. Methods and Results-ECE-1 localization was studied using confocal microscopy, which provides evidence for the first time that both ET-1 and ECE-1 a are also found in the nuclear compartment in transiently transfected cells as well as in native endothelial cells that endogenously possess the ET system. In cells maintained in high-glucose medium, ECE-1a-specific staining shifted from plasma membrane to intracellular compartments, ECE-1b subisoform, however, is mainly in the cytosolic compartment, indicating a subisoform specificity for nuclear localization. Conclusions-Our findings define a novel localization pattern for the ET system, which may be differentially regulated under pathophysiological conditions.