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Role of Carboxypeptidase E in Processing of Pro-Islet Amyloid Polypeptide in ß-Cells

Department of Pathology and Laboratory Medicine and British Columbia Research Institute for Children’s and Women’s Health, University of British Columbia, Vancouver, British Columbia, Canada V5Z 4H4

Address all correspondence and requests for reprints to: Dr. C. Bruce Verchere, British Columbia Research Institute for Children’s and Women’s Health, 3084-950 West 28th Avenue, Vancouver, British Columbia, Canada V5Z 4H4. E-mail: verchere{at}interchange.ubc.ca.

Islet amyloid polypeptide (IAPP; amylin) is a peptide hormone that is cosecreted with insulin from ß-cells. Impaired processing of proIAPP, the IAPP precursor, has been implicated in islet amyloid formation in type 2 diabetes. We previously showed that proIAPP is processed to IAPP by the prohormone convertases PC1/3 and PC2 at its carboxyl (COOH) and amino (NH₂) termini, respectively. In this study, we investigated the role of carboxypeptidase E (CPE) in the processing of proIAPP using mice lacking active CPE (Cpe^fat/Cpe^fat) and NIT-2 cells, a ß-cell line derived from their islets. Western blot analysis demonstrated that an approximately 6-kDa NH₂-terminally unprocessed form of proIAPP was elevated approximately 86% in islets from Cpe^fat/Cpe^fat mice, compared with wild type. This increase was independent of the development of hyperglycemia (8 wk male) or obesity (18 wk female). Impaired proIAPP processing was associated with a decrease in PC2 (but not PC1/3) and both the 21- and 27-kDa forms of the PC2 chaperone protein 7B2, suggesting that PC2-mediated processing of proIAPP at its NH₂ terminus was impaired in the absence of CPE. Formation of COOH-terminally amidated (pro)IAPP was reduced approximately 75% in NIT-2, compared with NIT-1 ß-cells, supporting a direct role for CPE in maturation of IAPP by removal of its COOH-terminal dibasic residues, the step essential for IAPP amidation. We conclude that lack of CPE in islet ß-cells results in a marked decrease in processing of proIAPP at its NH₂ (but not COOH) terminus that is associated with attenuated levels of PC2 and (pro)7B2 and a great reduction in formation of mature amidated IAPP.

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