Islet amyloid polypeptide triggers limited complement activation and binds complement inhibitor C4b-binding protein, which enhances fibril formation.

The Journal of Biological Chemistry
Jonatan SjölanderAnna M Blom

Abstract

Islet amyloid polypeptide (IAPP) is synthesized in pancreatic β-cells and co-secreted with insulin. Aggregation and formation of IAPP-amyloid play a critical role in β-cell death in type 2 diabetic patients. Because Aβ-fibrils in Alzheimer disease activate the complement system, we have here investigated specific interactions between IAPP and complement factors. IAPP fibrils triggered limited activation of complement in vitro, involving both the classical and the alternative pathways. Direct binding assays confirmed that IAPP fibrils interact with globular head domains of complement initiator C1q. Furthermore, IAPP also bound complement inhibitors factor H and C4b-binding protein (C4BP). Recombinant C4BP mutants were used to show that complement control protein (CCP) domains 8 and 2 of the α-chain were responsible for the strong, hydrophobic binding of C4BP to IAPP. Immunostaining of pancreatic sections from type 2 diabetic patients revealed the presence of complement factors in the islets and varying degree of co-localization between IAPP fibrils and C1q, C3d, as well as C4BP and factor H but not membrane attack complex. Furthermore, C4BP enhanced formation of IAPP fibrils in vitro. We conclude that C4BP binds to IAPP thereby ...Continue Reading

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Citations

Apr 19, 2013·PloS One·Camilla Melin FürstAnna M Blom
Dec 18, 2013·Arthritis Research & Therapy·Kaisa E OttebyAnna M Blom
Jul 31, 2014·The Journal of Experimental Medicine·Michael P KurnellasJonathan B Rothbard
Jan 27, 2015·Neuron·Marie-Victoire Guillot-SestierTerrence Town
Sep 25, 2015·Journal of Receptor and Signal Transduction Research·Song Mao, Jianhua Zhang
Dec 15, 2015·Immunology Letters·David Ermert, Anna M Blom
Nov 12, 2016·Nature Reviews. Endocrinology·A M James ShapiroCamillo Ricordi
Aug 28, 2016·The Journal of Biological Chemistry·Jonatan SjölanderAnna M Blom
Aug 11, 2019·Molecular Immunology·Ramzi A Ajjan, Verena Schroeder
Jun 24, 2021·Seminars in Immunopathology·B C King, A M Blom

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