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The novel sorting nexin SNX33 interferes with cellular PrPSc formation by modulation of PrPc shedding.
1116 - 1129.
The cellular prion protein (PrPc) is a glycosyl-phosphatidylinositol (GPI)-anchored protein trafficking in the secretory and endocytic pathway and localized mainly at the plasma membrane. Conversion of PrPc into its pathogenic isoform PrPSc is associated with pathogenesis and transmission of prion diseases. Intramolecular cleavage in the middle, the extreme C-terminal part or within the GPI anchor and shedding of PrPc modulate this conversion process by reducing the substrate for prion formation. These phenomena provide similarities with the processing of amyloid precursor protein in Alzheimer's disease. Sorting nexins are a family of proteins with important functions in protein trafficking. In this study, we investigated the role of the newly described sorting nexin 33 (SNX33) in trafficking and processing of PrPc. We found that overexpression of SNX33 in neuronal and non-neuronal cell lines resulted in increased shedding of full-length PrPc from the plasma membrane and modulated the rate of PrPc endocytosis. This was paralleled by reduction of PrPSc formation in persistently and newly infected cells. Using deletion mutants, we demonstrate that production of PrP fragment N1 is not influenced by SNX33. Our data provide new insights into the cellular mechanisms of PrPc shedding and show how this can affect cellular PrPSc conversion.
|Title:||The novel sorting nexin SNX33 interferes with cellular PrPSc formation by modulation of PrPc shedding|
|Keywords:||ADAM cleavage, prion, prion infection, PrP shedding, SNX33, sorting nexin, AMYLOID PRECURSOR PROTEIN, ANCHORED PRION PROTEIN, CLATHRIN-MEDIATED ENDOCYTOSIS, ALPHA-SECRETASE CLEAVAGE, SCRAPIE-ASSOCIATED FORM, CULTURED-CELLS, SOLUBLE FORM, SUBCELLULAR TRAFFICKING, PROTEOLYTIC CLEAVAGE, ALZHEIMERS-DISEASE|
|UCL classification:||UCL > School of Life and Medical Sciences
UCL > School of Life and Medical Sciences > Faculty of Life Sciences
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