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Impaired NH2-terminal processing of human proislet amyloid polypeptide by the prohormone convertase PC2 leads to amyloid formation and cell death

Marzban, Lucy
Rhodes, C. J.
Steiner, D. F.
Haataja, Leena
Verchere, C. B.
Published in Diabetes. 2006, vol. 55, no. 8, p. 2192-2201
Abstract Islet amyloid, formed by aggregation of islet amyloid polypeptide (IAPP; amylin), is a pathological characteristic of the pancreas in type 2 diabetes and may contribute to the progressive loss of beta-cells in this disease. We tested the hypothesis that impaired processing of the IAPP precursor proIAPP contributes to amyloid formation and cell death. GH3 cells lacking the prohormone convertase 1/3 (PC1/3) and IAPP and with very low levels of prohormone convertase 2 (PC2) were transduced with adenovirus (Ad) expressing human or rat (control) proIAPP linked to green fluorescent protein, with or without Ad-PC2 or Ad-PC1/3. Expression of human proIAPP increased the number of transferase-mediated dUTP nick-end labeling (TUNEL)-positive cells 96 h after transduction (+hIAPP 8.7 +/- 0.4% vs. control 3.0 +/- 0.4%; P < 0.05). COOH-terminal processing of human proIAPP by PC1/3 increased (hIAPP+PC1/3 10.4 +/- 0.7%; P < 0.05), whereas NH(2)-terminal processing of proIAPP by addition of PC2 markedly decreased (hIAPP+PC2 5.5 +/- 0.5%; P < 0.05) the number of apoptotic GH3 cells. Islets from mice lacking PC2 and with beta-cell expression of human proIAPP (hIAPP(+/+)/PC2(-/-)) developed amyloid associated with beta-cell death during 2-week culture. Rescue of PC2 expression by ex vivo transduction with Ad-PC2 restored NH(2)-terminal processing to mature IAPP and decreased both the extent of amyloid formation and the number of TUNEL-positive cells (-PC2 26.5 +/- 4.1% vs. +PC2 16.1 +/- 4.3%; P < 0.05). These findings suggest that impaired NH(2)-terminal processing of proIAPP leads to amyloid formation and cell death and that accumulation of the NH(2)-terminally extended human proIAPP intermediate may be a critical initiating step in amyloid formation.
Keywords Adenoviridae/geneticsAmyloid/ biosynthesis/genetics/metabolismAnimalsApoptosis/ physiologyCell LineGene ExpressionGreen Fluorescent Proteins/geneticsHumansIn Situ Nick-End LabelingIslets of Langerhans/ enzymologyMiceMice, Inbred C57BLMice, Inbred CBAMice, KnockoutMice, TransgenicPeptide Fragments/metabolismPituitary Gland, AnteriorProprotein Convertase 2/deficiency/genetics/ metabolismRatsRecombinant Fusion ProteinsTransfection
PMID: 16873681
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MARZBAN, Lucy et al. Impaired NH2-terminal processing of human proislet amyloid polypeptide by the prohormone convertase PC2 leads to amyloid formation and cell death. In: Diabetes, 2006, vol. 55, n° 8, p. 2192-2201. doi: 10.2337/db05-1566 https://archive-ouverte.unige.ch/unige:8885

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Deposited on : 2010-07-12

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