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Disruption of a Receptor-Mediated Mechanism for Intracellular Sorting of Proinsulin in Familial Hyperproinsulinemia

Section on Cellular Neurobiology (S.D., F.-S.S., T.A., C.Z., Y.P.L.), Laboratory of Developmental Neurobiology, National Institutes of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892-4480; Medivir U.K. Ltd. (C.R.S.), Cambridge CB1 9PT, United Kingdom; Creighton University School of Medicine (R.B.M.), Omaha, Nebraska 68178-0306; and Montreal Neurological Institute (S.J.M.), McGill University, Montreal, Quebec, Canada H3A 2B4

Address all correspondence and requests for reprints to: Y. Peng Loh, National Institutes of Health, Building 49, Room 5A38, MSC 4480, Bethesda, Maryland 20892-4480. E-mail: lohp{at}mail.nih.gov.

In familial hyperproinsulinemia, specific mutations in the proinsulin gene are linked with a profound increase in circulating plasma proinsulin levels. However, the molecular and cellular basis for this disease remains uncharacterized. Here we investigated how these mutations may disrupt the sorting signal required to target proinsulin to the secretory granules of the regulated secretory pathway, resulting in the unregulated release of proinsulin. Using a combination of molecular modeling and site-directed mutagenesis, we have identified structural molecular motifs in proinsulin that are necessary for correct sorting into secretory granules of endocrine cells. We show that membrane carboxypeptidase E (CPE), previously identified as a prohormone-sorting receptor, is essential for proinsulin sorting. This was demonstrated through short interfering RNA-mediated depletion of CPE and transfection with a dominant negative mutant of CPE in a ß-cell line. Mutant proinsulins found in familial hyperproinsulinemia failed to bind to CPE and were not sorted efficiently. These findings provide evidence that the elevation of plasma proinsulin levels found in patients with familial hyperproinsulinemia is caused by the disruption of CPE-mediated sorting of mutant proinsulins to the regulated secretory pathway.

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