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¹ Department of Microbiology and Molecular Medicine, University of Geneva, Geneva, Switzerland 1211
² Institute for Molecular Bioscience, Centre for Microscopy and Microanalysis, and Department of Physiology and Pharmacology, University of Queensland, Brisbane, Australia 4072
³ Microbial Pathogenesis Section, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892

Address correspondence to F. Gisou van der Goot, Dept. of Microbiology and Molecular Medicine, University of Geneva, 1 rue Michel Servet, Geneva, Switzerland 1211. Tel.: 41-22-379-5652. Fax: 41-22-379-5702. email: gisou.vandergoot{at}medecine.unige.ch

Abstract
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.

Key Words: diphtheria toxin; LBPA; ALIX; MAPK; multivesicular; COP

Abbreviations used in this paper: DT, diphtheria toxin; DTn, trypsin-nicked DT; -COP, COPI coatomer subunit; ECV/MVB, endosomal carrier vesicles/multivesicular bodies; EF, edema factor; EF-2, elongation factor 2; FP59, fusion protein 59; LBPA, lysobisphosphatidic acid; LF, lethal factor; MAPKK, MAPK kinase; PA, protective antigen; PAn, trypsin-nicked PA; PNS, postnuclear supernatants.

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