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Internalized Pseudomonas Exotoxin A can Exploit Multiple Pathways to Reach the Endoplasmic Reticulum
Author(s) -
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.
Publication year - 2006
Publication title -
traffic
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.677
H-Index - 130
eISSN - 1600-0854
pISSN - 1398-9219
DOI - 10.1111/j.1600-0854.2006.00391.x
Subject(s) - endoplasmic reticulum , biology , pseudomonas exotoxin , microbiology and biotechnology , exploit , pseudomonas aeruginosa , computational biology , bacteria , genetics , computer science , computer security
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 α2‐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.