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Soluble sulfated GAGs are known for their propensity to promote the self\u2010assembly of numerous amyloidogenic proteins and to modulate their cytotoxicity. Nonetheless, although GAGs are prevalent on the outer leaflet of eukaryotic cell plasma membrane as part of proteoglycans, their contributions in the perturbation of lipid bilayer induced by amyloid polypeptides remain unknown. Herein, we investigate the roles of GAGs in the cytotoxicity and plasma membrane perturbation induced by the islet amyloid polypeptide (IAPP), whose deposition in the pancreatic islets is associated with type II diabetes. Cellular assays using GAG\u2010deficient cells reveal that GAGs exacerbate IAPP\u2010induced cytotoxicity and permeabilization of the plasma membrane. Confocal microscopy and flow cytometry analyses show that IAPP sequestration at the cell surface is dependent of GAGs and of the aggregation propensity of the peptide. Using giant plasma membrane vesicles (GPMVs) prepared from GAG\u2010deficient cells, we investigate the direct contributions of membrane\u2010embedded proteoglycans in IAPP\u2010induced membrane disassembly. In sharp contrast to soluble sulfated GAGs, kinetics of amyloid self\u2010assembly expose that the presence of GAGs on GPMVs does not significantly modulate in vitro amyloid formation. Overall, this study indicates that cell surface GAGs increase the local concentration of IAPP in the vicinity of the plasma membrane, promoting lipid bilayer perturbation and cell death.<\/jats:p>","DOI":"10.1096\/fj.202001845r","type":"journal-article","created":{"date-parts":[[2021,1,21]],"date-time":"2021-01-21T13:53:54Z","timestamp":1611237234000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Cell surface glycosaminoglycans exacerbate plasma membrane perturbation induced by the islet amyloid polypeptide"],"prefix":"10.1096","volume":"35","author":[{"given":"No\u00e9","family":"Quittot","sequence":"first","affiliation":[{"name":"Department of Chemistry Universit\u00e9 du Qu\u00e9bec \u00e0 Montr\u00e9al Montreal QC Canada"},{"name":"Center of Excellence in Research on Orphan Diseases \u2010 Courtois Foundation Montreal Canada"},{"name":"Quebec Network for Research on Protein Function, Engineering and 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