Disruption of PC1/3 expression in mice causes dwarfism and multiple neuroendocrine peptide processing defects

Abstract

The subtilisin-like proprotein convertases PC1͞3 (SPC3) and PC2 (SPC2) are believed to be the major endoproteolytic processing enzymes of the regulated secretory pathway. They are expressed together or separately in neuroendocrine cells throughout the brain and dispersed endocrine system in both vertebrates and invertebrates. Disruption of the gene-encoding mouse PC1͞3 has now been accomplished and results in a syndrome of severe postnatal growth impairment and multiple defects in processing many hormone precursors, including hypothalamic growth hormone-releasing hormone (GHRH), pituitary proopiomelanocortin to adrenocorticotropic hormone, islet proinsulin to insulin and intestinal proglucagon to glucagon-like peptide-1 and -2. Mice lacking PC1͞3 are normal at birth, but fail to grow normally and are about 60% of normal size at 10 weeks. . The PC1͞3-null mice differ from a human subject reported with compound heterozygosity for defects in this gene, who was of normal stature but markedly obese from early life. The PC1͞3-null mice are not obese. The basis for these phenotypic differences is an interesting topic for further study. These findings prove the importance of PC1͞3 as a key neuroendocrine convertase.

Inhibition of Deoxyhypusine Synthase Enhances Islet β Cell Function and Survival in the Setting of Endoplasmic Reticulum Stress and Type 2 Diabetes

“…Interestingly, the increased ␤ cell mass in treated animals was correlated to a reduction in the fasting serum proinsulin:insulin ratio compared with untreated controls (Fig. 3C); this ratio has been suggested to re- flect ER capacity to properly fold and process proinsulin via the enzyme PC1/3, with higher ratios suggestive of a defect (27)(28)(29)(30)(31). These results suggest that inhibition of DHS preserves islet function and mass in the setting of obesity-related diabetes, possibly through effects on ER folding and processing capacity.…”

Adventures with Insulin in the Islets of Langerhans

“…On the other hand, mice null for PC1/3 displayed alterations in a different subset of neuroendocrine peptides, reflecting subtle differences in the tissue specificity of its expression compared with that of PC2 within neuroendocrine tissues (73). In contrast, disruptions of the genes encoding furin, PACE4, and PC5/6 (74), as well as PAM (75), the peptide-amidating monooxygenase that accomplishes the C-terminal amidation of many neuroendocrine peptides, all result in developmental defects that prevent the normal development of the fetus, usually through defective activation of various growth factors required for specific developmental processes.…”

Loss of prohormone convertase 2 promotes beta cell dysfunction in a rodent transplant model expressing human pro-islet amyloid polypeptide

“…Proinsulin processing is impaired in both type 2 diabetes [15][16][17] and islet transplants [18], resulting in elevated proinsulin:C-peptide ratios. Proinsulin processing involves cleavage by prohormone convertase (PC) 1/3 and PC2 in order to generate insulin and C-peptide [17,19]. In PC2-deficient mice, the absence of PC2 is partially compensated by the action of PC1/3 [20]; however, mice lacking PC2 still have elevated levels of proinsulin [21], a molecule with 10% bioactivity relative to insulin [22].…”

“…Partially processed proIAPP species form aggregate structures in vitro [25,26] and may be involved in amyloid formation and toxicity. Studying the effect of impaired prohormone processing has been limited by the lack of a suitable model, since global loss of PC2 results in developmental abnormalities [19,27] and hypoglycaemia [20,24].…”