Anthrax toxin triggers the activation of src-like kinases to mediate its own uptake.
AB-type toxins, like other bacterial toxins, are notably opportunistic molecules. They rely on target cell receptors to reach the appropriate location within the target cell where translocation of their enzymatic subunits occurs. The anthrax toxin, however, times its own uptake, suggesting that toxin binding triggers specific signaling events. Here we show that the anthrax toxin triggers tyrosine phosphorylation of its own receptors, capillary morphogenesis gene 2 and tumor endothelial marker 8, which are not endowed with intrinsic kinase activity. This is required for efficient toxin uptake because endocytosis of the mutant receptor lacking the cytoplasmic tyrosine residues is strongly delayed. Phosphorylation of the receptors was dependent on src-like kinases, which where activated upon toxin binding. Importantly, src-dependent phosphorylation of the receptor was required for its subsequent ubiquitination, which in turn was required for clathrin-mediated endocytosis. Consistently, we found that uptake of the anthrax toxin and processing of the lethal factor substrate MEK1 are inhibited by silencing of src and fyn, as well as in src and fyn knockout cells.
Abrami
Laurence
L
Global Health Institute, Ecole Polytechnique Fédérale de Lausanne, CH-1015 Lausanne, Switzerland.
Kunz
Béatrice
B
van der Goot
F Gisou
FG
D000818:Animals; D000942:Antigens, Bacterial / Q000378:metabolism*; D001427:Bacterial Toxins / Q000378:metabolism*; D002460:Cell Line; D006224:Cricetinae; D004705:Endocytosis; D004789:Enzyme Activation; D006801:Humans; D048369:MAP Kinase Kinase 1 / Q000378:metabolism; D051379:Mice; D019000:Phosphotyrosine / Q000378:metabolism; D011485:Protein Binding; D051076:Proto-Oncogene Proteins c-fyn / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D018000:Receptors, Peptide / Q000378:metabolism; D013379:Substrate Specificity; D054875:Ubiquitination; D019061:src-Family Kinases / Q000235:genetics / Q000378:metabolism*
D000942:Antigens, Bacterial; D001427:Bacterial Toxins; D034741:RNA, Small Interfering; D018000:Receptors, Peptide; C030325:anthrax toxin; C070309:anthrax toxin receptors; D019000:Phosphotyrosine; C494960:Fyn protein, mouse; D051076:Proto-Oncogene Proteins c-fyn; D019061:src-Family Kinases; D048369:MAP Kinase Kinase 1