Membrane translocation of diphtheria toxin fragment A exploits early to late endosome trafficking machinery.
After reaching early endosomes by receptor-mediated endocytosis, diphtheria toxin (DT) molecules have two possible fates. A large pool enters the degradative pathway whereas a few molecules become cytotoxic by translocating their catalytic fragment A (DTA) into the cytosol. Impairment of DT degradation by microtubule depolymerization does not block DT cytotoxicity. Therefore, DTA membrane translocation into the cytosol occurs from an endocytic compartment located upstream of late endosomes. Comparisons between early endosomes and endocytic carrier vesicles in a cell-free translocation assay have demonstrated that early endosomes are the earliest endocytic compartment from which DTA translocates. DTA translocation is ATP-dependent, requires early endosomal acidification, and is increased by the addition of cytosol. Cytosol-dependent DTA translocation is GTP gamma S-insensitive but is blocked by anti-beta COP antibodies.
Lemichez
E
E
INSERM U452 Faculté de Médecine, Nice, France.
Bomsel
M
M
Devilliers
G
G
vanderSpek
J
J
Murphy
J R
JR
Lukianov
E V
EV
Olsnes
S
S
Boquet
P
P
D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism; D002474:Cell-Free System; D003034:Coated Pits, Cell-Membrane; D018699:Coated Vesicles; D003600:Cytosol / Q000737:chemistry; D004167:Diphtheria Toxin / Q000502:physiology*; D004705:Endocytosis / Q000187:drug effects / Q000502:physiology; D011992:Endosomes / Q000378:metabolism*; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000494:pharmacology; D066298:In Vitro Techniques; D008247:Lysosomes / Q000378:metabolism; D008561:Membrane Fusion; D018613:Microscopy, Confocal; D008856:Microscopy, Fluorescence; D010446:Peptide Fragments / Q000502:physiology*
D002352:Carrier Proteins; D004167:Diphtheria Toxin; D010446:Peptide Fragments; C029795:diphtheria toxin fragment A; D016244:Guanosine 5'-O-(3-Thiotriphosphate)