Role of beta-cell prohormone convertase (PC)1/3 in processing of pro-islet amyloid polypeptide

Diabetes. 2004 Jan;53(1):141-8. doi: 10.2337/diabetes.53.1.141.

Abstract

Islet amyloid polypeptide (IAPP) (amylin), the major component of islet amyloid, is produced by cleavage at the COOH- and NH(2)-termini of its precursor, proIAPP, likely by the beta-cell prohormone convertases (PC) 1/3 and PC2. Mice lacking PC2 can process proIAPP at its COOH- but not its NH(2)-terminal cleavage site, suggesting that PC1/3 is capable of initiating proIAPP cleavage at its COOH-terminus. To determine the precise role of PC1/3 in proIAPP processing, Western blot analysis was performed on islets isolated from mice lacking PC1/3 (PC1/3(-/-)). These islets contained not only fully processed IAPP as in PC1/3(+/+) islets, but also elevated levels of a COOH-terminally unprocessed intermediate form, suggesting impaired processing at the COOH-terminus. Next, GH3 cells that do not normally express proIAPP or detectable levels of PC1/3 or PC2 were cotransduced with adenoviruses expressing rat proIAPP and either PC2 or PC1/3. As expected, in GH3 cells transduced to express only proIAPP, no processing was observed. Coexpression of proIAPP and PC2 resulted in production of mature IAPP, whereas in cells that coexpressed proIAPP and PC1/3 only a 6-kDa intermediate was produced. We conclude that PC1/3 is important for processing of proIAPP at the COOH-terminus, but in its absence, PC2 can initiate complete processing of proIAPP to IAPP by cleaving the precursor at either its NH(2)- or COOH-terminal cleavage sites.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyloid / metabolism*
  • Animals
  • Islet Amyloid Polypeptide
  • Islets of Langerhans / enzymology
  • Islets of Langerhans / physiology*
  • Mice
  • Mice, Knockout
  • Proprotein Convertase 1 / deficiency*
  • Proprotein Convertase 1 / genetics
  • Proprotein Convertase 1 / physiology*
  • Protein Processing, Post-Translational

Substances

  • Amyloid
  • Islet Amyloid Polypeptide
  • pro-islet amyloid polypeptide
  • Proprotein Convertase 1