The C-terminal Amphipathic Helix of Carboxypeptidase E Mediates Export from the ER and Secretion via Lysosomes.

Carboxypeptidase E (CPE), an essential enzyme in the biosynthetic production line of most peptide hormones and neuropeptides, is predominantly expressed in endocrine tissues and in the nervous system. CPE is active in acidic environments where it cleaves the C'-terminal basic residues of peptide precursors to generate their bioactive form. Consequently, this highly conserved enzyme regulates numerous fundamental biological processes. Here, we combined live-cell microscopy and molecular analysis to examine the intracellular distribution and secretion dynamics of fluorescently tagged CPE. We show that, in non-endocrine cells, tagged-CPE is a soluble luminal protein that is efficiently exported from the ER via the Golgi apparatus to lysosomes. The C'-terminal conserved amphipathic helix serves as a lysosomal and secretory granule targeting and a secretion motif. Following secretion, CPE may be reinternalized into the lysosomes of neighboring cells.