NR AVNV
AU Orsi,A.; Fioriti,L.; Chiesa,R.; Sitia,R.
TI Conditions of endoplasmic reticulum stress favor the accumulation of cytosolic prion protein
QU The Journal of Biological Chemistry 2006 Oct 13; 281(41): 30431-8
PT journal article; research support, non-u.s. gov't
AB After signal sequence-dependent targeting to the endoplasmic reticulum (ER), prion protein (PrP) undergoes several post-translational modifications, including glycosylation, disulfide bond formation, and the addition of a glycosylphosphatidylinositol anchor. As a result, multiple isoforms are generated. Because of the intrinsic weakness of the PrP signal sequence, a fraction of newly synthesized molecules fails to translocate and localizes to the cytosol. The physiopathologic role of this cytosolic isoform is still being debated. Here we have shown that, in both cultured cell lines and primary neurons, ER stress conditions weaken PrP co-translational translocation, favoring accumulation of aggregation-prone cytosolic species, which retain the signal sequence but lack N-glycans and disulfides. Inhibition of proteasomes further increases the levels of cytosolic PrP. Overexpression of spliced XBP1 facilitates ER translocation, suggesting that downstream elements of the Ire1-XBP1 pathway are involved in PrP targeting. These studies reveal a link between ER stress and the formation of cytosolic PrP isoforms potentially endowed with novel signaling or cytotoxic functions.
MH Animals; Cytosol/*metabolism; Disulfides; Endoplasmic Reticulum/*metabolism; Glycosylphosphatidylinositols/chemistry; Hela Cells; Humans; Mice; Neurons/metabolism; Prions/*metabolism; Proteasome Endopeptidase Complex/chemistry; Protein Isoforms; Protein Processing, Post-Translational; Xeroderma Pigmentosum Group A Protein/physiology
AD Universita Vita-Salute San Raffaele, DiBiT Istituto Scientifico San Raffaele, Via Olgettina 58, 20132 Milano, Italy.
SP englisch
PO USA