The biosynthesis of the subtilisin-related proprotein convertase PC3, but no that of the PC2 convertase, is regulated by glucose in parallel to proinsulin biosynthesis in rat pancreatic islets

Abstract

The biosynthesis of proinsulin is specifically stimulated by glucose in the pancreatic beta-cell, and this, in turn, places an increased demand on the mechanism for proinsulin to insulin conversion. Proteolytic proinsulin processing is catalyzed by two endopeptidases putatively identified as the subtilisin-related PC2 and PC3 convertases (Bennett, D. L., Bailyes, E. M., Nielson, E., Guest, P. C., Rutherford, N. G., Arden, S. D., and Hutton, J. C. (1992) J. Biol. Chem. 267, 15229-15236; Bailyes, E. M., Shennan, K. I. J., Seal, A. J., Smeekens, S. P., Steiner, D. F., Hutton, J. C., and Docherty, K. (1992) Biochem. J. 285, 391-394). In this study, we demonstrate in isolated rat pancreatic islets that the biosynthesis of PC3 was specifically stimulated by glucose relatively parallel to that of proinsulin. In contrast, however, PC2 biosynthesis was not glucose-regulated. The stimulation of PC3 and proinsulin biosynthesis was observed above a threshold of 4 mM glucose and reached a maximum (about 7-10-fold) above 10 mM glucose concentrations. Glucose stimulation for PC3 and proinsulin biosynthesis was rapid (occurring within 20 min and reaching a maximum by 60 min) and was not affected by the additional presence of actinomycin D, suggesting regulation predominantly at the translational level. Moreover, the intracellular signals for glucose-stimulated PC3 and proinsulin biosynthesis appeared to be similar, requiring the metabolism of glucose. PC3 has been implicated as the key endopeptidase in proinsulin to insulin conversion, in that it is the enzyme which preferentially initiates the process (Rhodes, C. J., Lincoln, B., and Shoelson, S. E. (1992) J. Biol. Chem. 267, 22719-22727). We suggest that co-ordinate stimulation of PC3 biosynthesis, along with that of its proinsulin substrate, elucidates an additional control point by which the mechanism of proprotein processing might be regulated.