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Emoto, N. et al.

Emoto, Nurhantari, Alimsardjono, Xie, Yamada, Yanagisawa, Matsuo,

Constitutive lysosomal targeting and degradation of bovine endothelin-converting enzyme-1a mediated by novel signals in its alternatively spliced cytoplasmic tail.

Endothelin-converting enzyme-1 (ECE-1) is a type II membrane protein that catalyzes the proteolytic activation of big endothelin-1 to endothelin-1 (ET-1). The subcellular distribution of ECE-1, and hence the exact site of physiological activation of big ET-1, remains controversial. Here, we demonstrate with several complementary methods that the two alternatively spliced bovine ECE-1 isoforms, ECE-1a and ECE-1b, differing only in the first 30 amino acids of their N-terminal cytoplasmic tails, exhibit strikingly distinct intracellular sorting patterns. Bovine ECE-1a, which is responsible for the intracellular cleavage of big ET-1 in endothelial cells, is constitutively recruited into the lysosome, where it is rapidly degraded. In contrast, bovine ECE-1b, the isoform found in cultured smooth muscle cells, is transported to the plasma membrane by a default pathway and functions as an ectoenzyme. Mutational analyses reveal that the N-terminal tip of the cytoplasmic domain of bovine ECE-1a contains novel proline-containing signals that mediate constitutive lysosomal targeting. Analyses of chimeric ECE-1/transferrin receptors demonstrate that the cytoplasmic tail of bovine ECE-1a is sufficient for the lysosomal delivery and rapid degradation. Our results suggest that the distinct intracellular targeting of bovine ECE-1 isoforms may provide new insights into functional aspect of the endothelin system and that the cell permeability of ECE inhibitor compounds should be carefully considered during their pharmacological development.[1]

References

Constitutive lysosomal targeting and degradation of bovine endothelin-converting enzyme-1a mediated by novel signals in its alternatively spliced cytoplasmic tail. Emoto, N., Nurhantari, Y., Alimsardjono, H., Xie, J., Yamada, T., Yanagisawa, M., Matsuo, M. J. Biol. Chem. (1999) [Pubmed]

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