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

Noriaki Emoto, Yudha Nurhantari, Haryanto Alimsardjono, Jian Xie, Takahisa Yamada, Masashi Yanagisawa, Masafumi Matsuo

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)1509-1518
Number of pages10
JournalJournal of Biological Chemistry
Volume274
Issue number3
DOIs
StatePublished - Jan 15 1999

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ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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