Receptor palmitoylation and ubiquitination regulate anthrax toxin endocytosis

• Published in: The Journal of cell biology Vol. 172; no. 2; pp. 309 - 320
• Main Authors: Abrami, Laurence, Leppla, Stephen H, van der Goot, F. Gisou
• Format: Journal Article
• Language: English
• Published: United States Rockefeller University Press 16.01.2006; The Rockefeller University Press
• Subjects: Amino Acid Sequence; Animals; Anthrax; Antibodies; Antigens, Bacterial - genetics; Antigens, Bacterial - metabolism; Bacterial Toxins - genetics; Bacterial Toxins - metabolism; Cell Line; Cell membranes; Cricetinae; Endocytosis; Endocytosis - physiology; Enzymes; Humans; Lipids; Membrane Microdomains - metabolism; Membrane Proteins - chemistry; Membrane Proteins - genetics; Membrane Proteins - metabolism; Molecular Sequence Data; Neoplasm Proteins - chemistry; Neoplasm Proteins - genetics; Neoplasm Proteins - metabolism; Palmitic Acid - metabolism; Peptides; Physiological regulation; Protein isoforms; Protein Isoforms - chemistry; Protein Isoforms - genetics; Protein Isoforms - metabolism; Protein Processing, Post-Translational; Protein Subunits - genetics; Protein Subunits - metabolism; Proto-Oncogene Proteins c-cbl - genetics; Proto-Oncogene Proteins c-cbl - metabolism; Rafts; Receptors; Receptors, Cell Surface - chemistry; Receptors, Cell Surface - genetics; Receptors, Cell Surface - metabolism; Receptors, Peptide; RNA, Small Interfering - metabolism; Sequence Alignment; Toxins; Ubiquitin - metabolism; Western blotting
• ISSN: 0021-9525; 1540-8140
• DOI: 10.1083/jcb.200507067

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.