Internalized Pseudomonas exotoxin A can exploit multiple pathways to reach the endoplasmic reticulum |
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Authors: | Smith Daniel C Spooner Robert A Watson Peter D Murray James L Hodge Thomas W Amessou Mohamed Johannes Ludger Lord J Michael Roberts Lynne M |
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Institution: | Molecular Cell Biology Group, Department of Biological Sciences, University of Warwick, Coventry CV4 7AL, UK. |
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Abstract: | Receptor-mediated internalization to the endoplasmic reticulum (ER) and subsequent retro-translocation to the cytosol are essential sequential processes required for the intoxication of mammalian cells by Pseudomonas exotoxin A (PEx). The toxin binds the alpha2-macroglobulin receptor/low-density lipoprotein receptor-related protein. Here, we show that in HeLa cells, PEx recruits a proportion of this receptor to detergent-resistant microdomains (DRMs). Uptake of receptor-bound PEx involves transport steps both directly from early endosomes to the trans-Golgi network (TGN) independently of Rab9 function and from late endosomes to the TGN in a Rab9-dependent manner. Furthermore, treatments that simultaneously perturb both Arf1-dependent and Rab6-dependent retrograde pathways show that PEx can use multiple routes to reach the ER. The Rab6-dependent route has only been described previously for cargo with lipid-sorting signals. These findings suggest that partial localization of PEx within DRM permits a choice of trafficking routes consistent with a model that DRM-associated toxins reach the ER on a lipid-dependent sorting pathway whilst non-DRM-associated PEx exploits the previously characterized KDEL receptor-mediated uptake pathway. Thus, unexpectedly, an ER-directed toxin with a proteinaceous receptor shows promiscuity in its intracellular trafficking pathways, exploiting routes controlled by both lipid- and protein-sorting signals. |
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Keywords: | COP I-dependent endoplasmic reticulum Pseudomonas exotoxin Rab6 Rab9 retrograde pathways |
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