title: BiP negatively affects ricin transport.
abstract: The AB plant toxin ricin binds both glycoproteins and glycolipids at the cell surface via its B subunit. After binding, ricin is endocytosed and then transported retrogradely through the Golgi to the endoplasmic reticulum (ER). In the ER, the A subunit is retrotranslocated to the cytosol in a chaperone-dependent process, which is not fully explored. Recently two separate siRNA screens have demonstrated that ER chaperones have implications for ricin toxicity. ER associated degradation (ERAD) involves translocation of misfolded proteins from ER to cytosol and it is conceivable that protein toxins exploit this pathway. The ER chaperone BiP is an important ER regulator and has been implicated in toxicity mediated by cholera and Shiga toxin. In this study, we have investigated the role of BiP in ricin translocation to the cytosol. We first show that overexpression of BiP inhibited ricin translocation and protected cells against the toxin. Furthermore, shRNA-mediated depletion of BiP enhanced toxin translocation resulting in increased cytotoxicity. BiP-dependent inhibition of ricin toxicity was independent of ER stress. Our findings suggest that in contrast to what was shown with the Shiga toxin, the presence of BiP does not facilitate, but rather inhibits the entry of ricin into the cytosol.
authors.affiliation: Department of Biosciences, and Centre for Immune Regulation, University of Oslo, Oslo 0316, Norway. t.f.gregers@ibv.uio.no
authors.forename: Tone F
authors.initials: TF
authors.lastname: Gregers
authors.forename: Sigrid S
authors.initials: SS
authors.lastname: Skånland
authors.forename: Sébastien
authors.initials: S
authors.lastname: Wälchli
authors.forename: Oddmund
authors.initials: O
authors.lastname: Bakke
authors.forename: Kirsten
authors.initials: K
authors.lastname: Sandvig
mesh_terms: D001692:Biological Transport; D003600:Cytosol / Q000378:metabolism; D000091342:Endoplasmic Reticulum Chaperone BiP; D057809:HEK293 Cells; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D012276:Ricin / Q000378:metabolism* / Q000633:toxicity
chemical_list: D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins; D012276:Ricin