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.

Complement inhibitor CD55 governs the integrity of membrane rafts in pancreatic beta cells, but plays no role in insulin secretion

“…3D). Taken together, these results fail to support a role for CD55 in the control of insulin secretion and point out an interesting dichotomy between CD55 and CD59 [10] as to their roles in this respect.…”

“…1A). A recent publication has shown that CD55 is expressed in pancreatic human islets and also in Wistar and diabetic GK rat islets [10]. Further, in the same study it was observed that expression of CD55 had a tendency for increase in the diabetic (GK) rat islets as compared to the healthy control (Wistar) islets.…”

“…Membrane rafts are highly dynamic structures with a high degree of lateral mobility in the loosely ordered membrane glycerophospholipids and are enriched in signaling proteins, as well as exocytotic signaling protein such as SNARE protein [9]. Furthermore, a recent study has deciphered the role of another GPI anchored complement inhibitor CD59 in regulation of membrane raft integrity and for insulin exocytosis [10]. Interestingly, CD55 is also localized to the membrane rafts areas in a variety of cells [11] and therefore we here studied whether CD55 may play analogous roles in membrane rafts formation and pancreatic islet functions.…”

Protective responses to sublytic complement in the retinal pigment epithelium

“…Because vitamin A dimers cause cholesterol accumulation in the RPE (20,21), they could potentially interfere with CD59 trafficking. To follow CD59 recycling, we treated RPE monolayers with phosphatidylinositol-specific phospholipase C (PI-PLC), which removes cell surface GPI-APs such as CD59 (23). Cell surface CD59 was completely restored ∼60 min after In the x-z images, ZO-1 (red) demarcates apical (Ap) and basolateral (Bl) cell membranes.…”

Dipeptidyl peptidase 4 (DPP-4) is expressed in mouse and human islets and its activity is decreased in human islets from individuals with type 2 diabetes

“…Formaldehyde-fixed, paraffinembedded mouse pancreatic sections (5 μm thick) were obtained from mice fed with ND or HFD (for 16 weeks) as well as Gcgr −/− mice. After dewaxing of the sections, the antibody- Analysis of gene expression Gene expression analysis was carried out by microarray on cDNA from islets of 23 type 2 diabetic donors and 23 non-diabetic donors matched for age, sex and BMI, using the Affymetrix GeneChip Human Gene 1.0 ST whole-transcript assay as previously described [18,19]. The data were summarised and normalised with the robust multi-array analysis method using the Expression Console software package (Affymetrix, Santa Clara, CA, USA).…”