K.B. and K.M. contributed equally to this work.
Involvement of glypican-1 autoprocessing in scrapie infection
Article first published online: 20 AUG 2008
© The Authors (2008). Journal Compilation © Federation of European Neuroscience Societies and Blackwell Publishing Ltd
European Journal of Neuroscience
Volume 28, Issue 5, pages 964–972, September 2008
How to Cite
Löfgren, K., Cheng, F., Fransson, L.-Å., Bedecs, K. and Mani, K. (2008), Involvement of glypican-1 autoprocessing in scrapie infection. European Journal of Neuroscience, 28: 964–972. doi: 10.1111/j.1460-9568.2008.06386.x
- Issue published online: 26 AUG 2008
- Article first published online: 20 AUG 2008
- Received 9 January 2008, revised 13 June 2008, accepted 30 June 2008
- heparan sulphate;
- nitric oxide;
The copper-binding cellular prion protein (PrPC) and the heparan sulphate (HS)-containing proteoglycan glypican-1 (Gpc-1) can both be attached to lipid rafts via their glycosylphosphatidylinositol anchors, and copper ions stimulate their cointernalization from the cell surface to endosomes. The prion protein controls cointernalization and delivers copper necessary for S-nitrosylation of conserved cysteines in the Gpc-1 core protein. Later, during recycling through endosomal compartments, nitric oxide can be released from the S-nitroso groups and catalyses deaminative degradation and release of the HS substituents. Here, by using confocal immunofluorescence microscopy, we show that normal PrPC and Gpc-1 colocalize inside GT1-1 cells. However, in scrapie-infected cells (ScGT1-1), Gpc-1 protein remained at the cell surface separate from the cellular prion protein. Scrapie infection stimulated Gpc-1 autoprocessing and the generated HS degradation products colocalized with intracellular aggregates of the disease-related scrapie prion protein isoform (PrPSc). Coimmunoprecipitation experiments demonstrated an association between Gpc-1 and PrPC in uninfected cells, and between HS degradation products and PrPSc in infected cells. Silencing of Gpc-1 expression or prevention of Gpc-1 autoprocessing elevated the levels of intracellular PrPSc aggregates in infected cells. These results suggest a role for Gpc-1 autoprocessing in the clearance of PrPSc from infected cells.