Membrane insertion of anthrax protective antigen and cytoplasmic delivery of lethal factor occur at different stages of the endocytic pathway.
The protective antigen (PA) of anthrax toxin binds to a cell surface receptor, undergoes heptamerization, and binds the enzymatic subunits, the lethal factor (LF) and the edema factor (EF). The resulting complex is then endocytosed. Via mechanisms that depend on the vacuolar ATPase and require membrane insertion of PA, LF and EF are ultimately delivered to the cytoplasm where their targets reside. Here, we show that membrane insertion of PA already occurs in early endosomes, possibly only in the multivesicular regions, but that subsequent delivery of LF to the cytoplasm occurs preferentially later in the endocytic pathway and relies on the dynamics of internal vesicles of multivesicular late endosomes.
Abrami
Laurence
L
Department of Microbiology and Molecular Medicine, University of Geneva, 1 rue Michel Servet, Geneva, Switzerland 1211.
Lindsay
Margaret
M
Parton
Robert G
RG
Leppla
Stephen H
SH
van der Goot
F Gisou
FG
D000818:Animals; D000881:Anthrax / Q000378:metabolism*; D000942:Antigens, Bacterial / Q000378:metabolism* / Q000494:pharmacology; D001427:Bacterial Toxins / Q000378:metabolism* / Q000494:pharmacology; D016466:CHO Cells; D022181:COP-Coated Vesicles; D002462:Cell Membrane / Q000378:metabolism* / Q000648:ultrastructure; D006224:Cricetinae; D003593:Cytoplasm / Q000378:metabolism* / Q000648:ultrastructure; D004705:Endocytosis / Q000502:physiology*; D006367:HeLa Cells; D006801:Humans; D048369:MAP Kinase Kinase 1; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D008854:Microscopy, Electron; D020929:Mitogen-Activated Protein Kinase Kinases / Q000187:drug effects / Q000378:metabolism; D021122:Protein Subunits / Q000378:metabolism; D022161:Transport Vesicles / Q000378:metabolism / Q000648:ultrastructure; D025262:Vacuolar Proton-Translocating ATPases / Q000378:metabolism; D020691:rab GTP-Binding Proteins
D000942:Antigens, Bacterial; D001427:Bacterial Toxins; D021122:Protein Subunits; C030325:anthrax toxin; D048369:MAP Kinase Kinase 1; C482125:MAP2K1 protein, human; D020929:Mitogen-Activated Protein Kinase Kinases; D025262:Vacuolar Proton-Translocating ATPases; D020691:rab GTP-Binding Proteins