title: Accumulating evidence suggests that several AB-toxins subvert the endoplasmic reticulum-associated protein degradation pathway to enter target cells.
abstract: Several AB-toxins appear to have independently evolved mechanisms by which they undergo retrograde transport from the cell membrane to the endoplasmic reticulum (ER). Recent insights into ER-associated protein degradation (ERAD) now provide clues as to why these toxins have selected the ER as the site of cell entry. We propose that they disguise themselves as misfolded proteins to enter the ERAD pathway. We further link the observation that these toxins have few, if any, lysine residues to the need to escape ubiquitin-mediated protein degradation, the ultimate destination of the ERAD pathway. The actual membrane translocation step remains unclear, but studies on viral immune evasion mechanisms indicate that retrotranslocation across the ER lipid bilayer may involve SEC61. Understanding the internalization process of these toxins opens new avenues for preventing their entry into cells. In addition, this knowledge can be exploited to create protein-based pharmaceuticals that act on cytosolic targets.
authors.affiliation: Department of Medical Microbiology and Immunology, University of Alberta, 1-41 Medical Sciences Building, Edmunton, Alberta, Canada T6G 2H7.
authors.forename: B
authors.initials: B
authors.lastname: Hazes
authors.forename: R J
authors.initials: RJ
authors.lastname: Read
mesh_terms: D000595:Amino Acid Sequence; D001427:Bacterial Toxins / Q000737:chemistry / Q000378:metabolism*; D001692:Biological Transport; D003587:Cytomegalovirus / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D006056:Golgi Apparatus / Q000378:metabolism; D008239:Lysine / Q000032:analysis; D008969:Molecular Sequence Data; D017510:Protein Folding; D011506:Proteins / Q000378:metabolism*; D016601:RNA-Binding Proteins / Q000378:metabolism; D012276:Ricin / Q000737:chemistry / Q000378:metabolism*; D014764:Viral Proteins / Q000378:metabolism
chemical_list: D001427:Bacterial Toxins; D011506:Proteins; D016601:RNA-Binding Proteins; C074546:US11 protein, herpesvirus; D014764:Viral Proteins; D012276:Ricin; D008239:Lysine