title: The complement inhibitor CD59 regulates insulin secretion by modulating exocytotic events.
abstract: Type 2 diabetes is triggered by reduced insulin production, caused by genetic and environmental factors such as inflammation originating from the innate immune system. Complement proteins are a component of innate immunity and kill non-self cells by perforating the plasma membrane, a reaction prevented by CD59. Human pancreatic islets express CD59 at very high levels. CD59 is primarily known as a plasma membrane protein in membrane rafts, but most CD59 protein in pancreatic β cells is intracellular. Removing extracellular CD59 disrupts membrane rafts and moderately stimulates insulin secretion, whereas silencing intracellular CD59 markedly suppresses regulated secretion by exocytosis, as demonstrated by TIRF imaging. CD59 interacts with the exocytotic proteins VAMP2 and Syntaxin-1. CD59 expression is reduced by glucose and in rodent diabetes models but upregulated in human diabetic islets, potentially reflecting compensatory reactions. This unconventional action of CD59 broadens the established view of innate immunity in type 2 diabetes.
authors.affiliation: Lund University Diabetes Center, Department of Clinical Sciences Malmö, Lund University, SE-205 02 Malmö, Sweden.
authors.forename: Ulrika
authors.initials: U
authors.lastname: Krus
authors.affiliation: Department of Laboratory Medicine Malmö, Lund University, SE-205 02 Malmö, Sweden.
authors.forename: Ben C
authors.initials: BC
authors.lastname: King
authors.affiliation: Lund University Diabetes Center, Department of Clinical Sciences Malmö, Lund University, SE-205 02 Malmö, Sweden.
authors.forename: Vini
authors.initials: V
authors.lastname: Nagaraj
authors.affiliation: Department of Medical Cell Biology, Uppsala University, Box 571, SE-751 23 Uppsala, Sweden.
authors.forename: Nikhil R
authors.initials: NR
authors.lastname: Gandasi
authors.affiliation: Department of Laboratory Medicine Malmö, Lund University, SE-205 02 Malmö, Sweden.
authors.forename: Jonatan
authors.initials: J
authors.lastname: Sjölander
authors.affiliation: Lund University Diabetes Center, Department of Clinical Sciences Malmö, Lund University, SE-205 02 Malmö, Sweden.
authors.forename: Pawel
authors.initials: P
authors.lastname: Buda
authors.affiliation: Lund University Diabetes Center, Department of Clinical Sciences Malmö, Lund University, SE-205 02 Malmö, Sweden.
authors.forename: Eliana
authors.initials: E
authors.lastname: Garcia-Vaz
authors.affiliation: Lund University Diabetes Center, Department of Clinical Sciences Malmö, Lund University, SE-205 02 Malmö, Sweden.
authors.forename: Maria F
authors.initials: MF
authors.lastname: Gomez
authors.affiliation: Lund University Diabetes Center, Department of Clinical Sciences Malmö, Lund University, SE-205 02 Malmö, Sweden.
authors.forename: Emilia
authors.initials: E
authors.lastname: Ottosson-Laakso
authors.affiliation: Lund University Diabetes Center, Department of Clinical Sciences Malmö, Lund University, SE-205 02 Malmö, Sweden.
authors.forename: Petter
authors.initials: P
authors.lastname: Storm
authors.affiliation: Lund University Diabetes Center, Department of Clinical Sciences Malmö, Lund University, SE-205 02 Malmö, Sweden.
authors.forename: Malin
authors.initials: M
authors.lastname: Fex
authors.affiliation: Lund University Diabetes Center, Department of Clinical Sciences Malmö, Lund University, SE-205 02 Malmö, Sweden.
authors.forename: Petter
authors.initials: P
authors.lastname: Vikman
authors.affiliation: Lund University Diabetes Center, Department of Clinical Sciences Malmö, Lund University, SE-205 02 Malmö, Sweden.
authors.forename: Enming
authors.initials: E
authors.lastname: Zhang
authors.affiliation: Department of Medical Cell Biology, Uppsala University, Box 571, SE-751 23 Uppsala, Sweden.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Barg
authors.affiliation: Department of Laboratory Medicine Malmö, Lund University, SE-205 02 Malmö, Sweden. Electronic address: anna.blom@med.lu.se.
authors.forename: Anna M
authors.initials: AM
authors.lastname: Blom
authors.affiliation: Lund University Diabetes Center, Department of Clinical Sciences Malmö, Lund University, SE-205 02 Malmö, Sweden. Electronic address: erik.renstrom@med.lu.se.
authors.forename: Erik
authors.initials: E
authors.lastname: Renström
mesh_terms: D000818:Animals; D018957:CD59 Antigens / Q000378:metabolism*; D002462:Cell Membrane / Q000378:metabolism; D003165:Complement System Proteins / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism; D005089:Exocytosis / Q000502:physiology*; D005947:Glucose / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D051381:Rats; D011913:Rats, Inbred BB; D017208:Rats, Wistar; D050827:Syntaxin 1 / Q000378:metabolism; D050988:Vesicle-Associated Membrane Protein 2 / Q000378:metabolism
chemical_list: D018957:CD59 Antigens; D007328:Insulin; D008565:Membrane Proteins; D050827:Syntaxin 1; D050988:Vesicle-Associated Membrane Protein 2; D003165:Complement System Proteins; D005947:Glucose