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Enming Zhang

Research team manager

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A cryptic non-GPI-anchored cytosolic isoform of CD59 controls insulin exocytosis in pancreatic β-cells by interaction with SNARE proteins

Author

  • Ewelina Golec
  • Rebecca Rosberg
  • Enming Zhang
  • Erik Renström
  • Anna M Blom
  • Ben C King

Summary, in English

CD59 is a glycosylphosphatidylinositol (GPI)-anchored cell surface inhibitor of the complement membrane attack complex (MAC). We showed previously that CD59 is highly expressed in pancreatic islets but is down-regulated in rodent models of diabetes. CD59 knockdown but not enzymatic removal of cell surface CD59 led to a loss of glucose-stimulated insulin secretion (GSIS), suggesting that an intracellular pool of CD59 is required. In this current paper, we now report that non-GPI-anchored CD59 is present in the cytoplasm, colocalizes with exocytotic protein vesicle-associated membrane protein 2, and completely rescues GSIS in cells lacking endogenous CD59 expression. The involvement of cytosolic non-GPI-anchored CD59 in GSIS is supported in phosphatidylinositol glycan class A knockout GPI anchor-deficient β-cells, in which GSIS is still CD59 dependent. Furthermore, site-directed mutagenesis demonstrated different structural requirements of CD59 for its 2 functions, MAC inhibition and GSIS. Our results suggest that CD59 is retrotranslocated from the endoplasmic reticulum to the cytosol, a process mediated by recognition of trimmed N-linked oligosaccharides, supported by the partial glycosylation of non-GPI-anchored cytosolic CD59 as well as the failure of N-linked glycosylation site mutant CD59 to reach the cytosol or rescue GSIS. This study thus proposes the previously undescribed existence of non-GPI-anchored cytosolic CD59, which is required for insulin secretion.-Golec, E., Rosberg, R., Zhang, E., Renström, E., Blom, A. M., King, B. C. A cryptic non-GPI-anchored cytosolic isoform of CD59 controls insulin exocytosis in pancreatic β-cells by interaction with SNARE proteins.

Department/s

  • EXODIAB: Excellence of Diabetes Research in Sweden
  • Protein Chemistry, Malmö
  • Brain Tumor Biology
  • Division of Translational Cancer Research
  • NanoLund: Center for Nanoscience
  • Diabetes - Islet Patophysiology
  • BioCARE: Biomarkers in Cancer Medicine improving Health Care, Education and Innovation

Publishing year

2019-11

Language

English

Pages

12425-12434

Publication/Series

FASEB journal : official publication of the Federation of American Societies for Experimental Biology

Volume

33

Issue

11

Document type

Journal article

Publisher

The Federation of American Societies for Experimental Biology

Topic

  • Endocrinology and Diabetes

Keywords

  • Animals
  • CD59 Antigens/genetics
  • CHO Cells
  • Cricetulus
  • Cytosol/metabolism
  • Exocytosis
  • Insulin/genetics
  • Insulin Secretion
  • Insulin-Secreting Cells/cytology
  • Oligosaccharides/genetics
  • Rats
  • SNARE Proteins/genetics

Status

Published

Research group

  • Protein Chemistry, Malmö
  • Brain Tumor Biology
  • Diabetes - Islet Patophysiology

ISBN/ISSN/Other

  • ISSN: 1530-6860