ACCUMULATING EVIDENCE SUGGESTS THAT SEVERAL AB-TOXINS SUBVERT THE ENDOPLASMIC RETICULUM-ASSOCIATED PROTEIN-DEGRADATION PATHWAY TO ENTER TARGET-CELLS

Several AB-toxins appear to have independently evolved mechanisms by w hich they undergo retrograde transport from the cell membrane to the e ndoplasmic reticulum (ER). Recent insights into ER-associated protein degradation (ERAD) now provide clues as to why these toxins have selec ted the ER as the site of cell entry. We propose that they disguise th emselves as misfolded proteins to enter the ERAD pathway. We further l ink the observation that these toxins have few, if any, lysine residue s to the need to escape ubiquitin-mediated protein degradation, the ul timate destination of the ERAD pathway. The actual membrane translocat ion step remains unclear, but studies on viral immune evasion mechanis ms indicate that retrotranslocation across the ER lipid bilayer may in volve 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 pharmaceutica ls that act on cytosolic targets.