Receptor palmitoylation and ubiquitination regulate anthrax toxin endocytosis.
The anthrax toxin is composed of three independent polypeptide chains. Successful intoxication only occurs when heptamerization of the receptor-binding polypeptide, the protective antigen (PA), allows binding of the two enzymatic subunits before endocytosis. We show that this tailored behavior is caused by two counteracting posttranslational modifications in the cytoplasmic tail of PA receptors. The receptor is palmitoylated, and this unexpectedly prevents its association with lipid rafts and, thus, its premature ubiquitination. This second modification, which is mediated by the E3 ubiquitin ligase Cbl, only occurs in rafts and is required for rapid endocytosis of the receptor. As a consequence, cells expressing palmitoylation-defective mutant receptors are less sensitive to anthrax toxin because of a lower number of surface receptors as well as premature internalization of PA without a requirement for heptamerization.
Abrami
Laurence
L
Department of Microbiology and Molecular Medicine, University of Geneva, 1211 Geneva 4, Switzerland.
Leppla
Stephen H
SH
van der Goot
F Gisou
FG
D000595:Amino Acid Sequence; D000818:Animals; D000942:Antigens, Bacterial / Q000235:genetics / Q000378:metabolism*; D001427:Bacterial Toxins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D006224:Cricetinae; D004705:Endocytosis / Q000502:physiology*; D006801:Humans; D021962:Membrane Microdomains / Q000378:metabolism; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D008840:Microfilament Proteins; D008969:Molecular Sequence Data; D009363:Neoplasm Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D019308:Palmitic Acid / Q000378:metabolism*; D020033:Protein Isoforms / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism*; D050721:Proto-Oncogene Proteins c-cbl / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D018000:Receptors, Peptide; D016415:Sequence Alignment; D025801:Ubiquitin / Q000378:metabolism*
C473287:ANTXR1 protein, human; C447150:ANTXR2 protein, human; D000942:Antigens, Bacterial; D001427:Bacterial Toxins; D008565:Membrane Proteins; D008840:Microfilament Proteins; D009363:Neoplasm Proteins; D020033:Protein Isoforms; D021122:Protein Subunits; D034741:RNA, Small Interfering; D011956:Receptors, Cell Surface; D018000:Receptors, Peptide; D025801:Ubiquitin; C030325:anthrax toxin; D019308:Palmitic Acid; D050721:Proto-Oncogene Proteins c-cbl