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Severe Block in Processing of Proinsulin to Insulin Accompanied by Elevation of Des-64,65 Proinsulin Intermediates in Islets of Mice Lacking Prohormone Convertase 1/3
Xiaorong Zhu, Lelio Orci, Raymond Carroll, Christina Norrbom, Mariella Ravazzola and Donald F. Steiner
Proceedings of the National Academy of Sciences of the United States of America
Vol. 99, No. 16 (Aug. 6, 2002), pp. 10299-10304
Published by: National Academy of Sciences
Stable URL: http://www.jstor.org/stable/3059384
Page Count: 6
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The neuroendocrine processing endoproteases PC2 and PC1/3 are expressed in the β cells of the islets of Langerhans and participate in the processing of proinsulin to insulin and C-peptide. We have previously shown that disruption of PC2 (SPC2) expression significantly impairs proinsulin processing. Here we report that disruption of the expression of PC1/3 (SPC3) produces a much more severe block in proinsulin conversion. In nulls, pancreatic and circulating proinsulin-like components comprise 87% and 91%, respectively, of total insulin-related immunoreactivity. Heterozygotes also show a more than 2-fold elevation in proinsulin levels to ≈12 %. Immunocytochemical and ultrastructural studies of the β cells reveal the nearly complete absence of mature insulin immunoreactivity and its replacement by that of proinsulin in abundant immature-appearing secretory granules. In contrast, α cell morphology and glucagon processing are normal, and there is also no defect in somatostatin-14 generation. Pulse-chase labeling studies confirm the existence of a major block in proinsulin processing in PC1/3 nulls with prolongation of half-times of conversion by 7- and 10-fold for proinsulins I and II, respectively. Lack of PC1/3 also results in increased levels of des-64,65 proinsulin intermediates generated by PC2, in contrast to PC2 nulls, in which des31,32 proinsulin intermediates predominate. These results confirm that PC1/3 plays a major role in processing proinsulin, but that its coordinated action with PC2 is necessary for the most efficient and complete processing of this prohormone.
Proceedings of the National Academy of Sciences of the United States of America © 2002 National Academy of Sciences