Depletion of carboxypeptidase E, a regulated secretory pathway sorting receptor, causes misrouting and constitutive secretion of proinsulin and proenkephalin, but not chromogranin A

Endocrinology
E Normant, Y P Loh

Abstract

Previous studies have shown that the prohormone POMC is sorted to the regulated secretory pathway (RSP), at the trans-Golgi network, by binding of a conformation-dependent sorting signal to a sorting receptor, identified as membrane-bound carboxypeptidase E (CPE) (Cool et al., 1997, Cell, 88:73-83). In this study, the role of CPE as a sorting receptor for other RSP proteins that contain sorting signals (proinsulin, proenkephalin, and chromogranin A) was investigated in neuroendocrine cells (Neuro-2a) stably expressing CPE antisense RNA. Whereas these cells were depleted of CPE by greater than 85%, electron microscopy showed that they contain dense core secretory granules identical to wild-type Neuro-2a cells, indicating that CPE is not essential for granulogenesis. Secretion and immunocytochemical studies showed that, in wild-type Neuro-2a cells, endogenous proenkephalin and transfected proinsulin/insulin were localized to punctate secretory granules and were released via the RSP. However, in CPE-depleted cells, these two prohormones were released constitutively and had a Golgi-like distribution but were not localized to punctate secretory granules. In contrast, chromogranin A was present in punctate secretory granules and rele...Continue Reading

Citations

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