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This version published online on June 26, 2003
Molecular Endocrinology, doi:10.1210/me.2002-0380
A more recent version of this article appeared on September 1, 2003
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Submitted on November 18, 2002
Accepted on June 16, 2003

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

Savita Dhanvantari1, Fu-Sheng Shen1, Tiffany Adams1, Chris. R. Snell1, ChunFa Zhang1, Robert B. Mackin1, Stephen J. Morris1, and Y. Peng Loh1*

1 Section on Cellular Neurobiology, Laboratory of Developmental Neurobiology, National Institutes of Child Health and Human Development, NIH, Bethesda, Maryland, USA; Medivir U.K. Ltd., Cambridge, CB1 9PT, U.K.; Creighton University School of Medicine, Omaha, Nebraska, USA; Montreal Neurological Institute, McGill University, Montreal, Quebec, H3A 2B4, Canada

* To whom correspondence should be addressed. 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, previously identified as a prohormone sorting receptor, is essential for proinsulin sorting. This was demonstrated through siRNA-mediated depletion of carboxypeptidase E and transfection with a dominant negative mutant of carboxypeptidase E in a {beta} cell line. Mutant proinsulins found in familial hyperproinsulinemia failed to bind to carboxypeptidase E 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 carboxypeptidase E-mediated sorting of mutant proinsulins to the regulated secretory pathway.
Key words: proinsulin • carboxypeptidase E • hyperproinsulinemia • receptor • sorting




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