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J Biol Chem, Vol. 273, Issue 6, 3431-3437, February 6, 1998
From the The prohormone convertases PC2 (SPC2)
and PC3/PC1 (SPC3) are the major precursor processing endoproteases in
a wide variety of neural and endocrine tissues. Both enzymes are
normally expressed in the islet beta cells and participate in
proinsulin processing. Recently we generated mice lacking active PC2
due to a disruption of the PC2 gene (Furuta, M., Yano, H., Zhou, A.,
Rouillé, Y., Holst, J. J., Carroll, R. J., Ravazzola,
M., Orci, L., Furuta, H., and Steiner, D. F. (1997) Proc.
Natl. Acad. Sci. U. S. A. 94, 6646-6651). Here we report that
these PC2 mutant mice have elevated circulating proinsulin, comprising
60% of immunoreactive insulin-like components. Acid ethanol
extractable proinsulin from pancreas is also significantly elevated,
representing about 35% of total immunoreactive insulin-like
components. These increased amounts of proinsulin are mainly stored in
secretory granules, giving rise to an altered appearance on electron
microscopy. In pulse-chase experiments, the mutant islets incorporate
lesser amounts of isotopic amino acids into insulin-related components than normal islets. In both wild-type and mutant islets, proinsulin I
was processed more rapidly to insulin, reflecting the preference of
both PC2 and PC3 for substrates having a basic amino acid positioned four residues upstream of the cleavage site. The overall half-time for
the conversion of proinsulin to insulin is increased approximately 3-fold in the mutant islets and is associated with a 4-5-fold greater
elevation of des-31,32 proinsulin, an intermediate that is formed by
the preferential cleavage of proinsulin at the B chain-C-peptide
junction by PC3 and is C-terminally processed to remove
Arg31 and Arg32 by carboxypeptidase E. The
constitutive release of newly synthesized proinsulin from both mutant
and wild-type islets during the first 1-2 h of chase was normal (<2%
of total). These results demonstrate that PC2 plays an essential role
in proinsulin processing in vivo, but is quantitatively
less important in this regard than PC3, and that its absence does not
influence the efficient sorting of proinsulin into the regulated
secretory pathway.
Incomplete Processing of Proinsulin to Insulin Accompanied by
Elevation of Des-31,32 Proinsulin Intermediates in Islets of Mice
Lacking Active PC2
,
,¶
Departments of Biochemistry and Molecular
Biology, Molecular Genetics and Cell Biology, and the
¶ Howard Hughes Medical Institute, University of Chicago, Chicago,
Illinois 60637, and the ** Department of Morphology, University of
Geneva, 1 Rue de Michel-Servet, 1211 4, Geneva, Switzerland
Copyright © 1998 by The American Society for Biochemistry and Molecular Biology, Inc.
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