Pathways of binding, internalization, and processing by immunotoxins leading to the killing of target cells. Shown are ricin-, Pseudomonas- and diphtheria-based immunotoxins. Immunotoxins bind the target antigen, are internalized via clathrin-coated pits, and are processed within endosomal compartments. Ricin and Pseudomonas toxin derivatives must traffic through the endoplasmic reticulum to the cytosol where they enzymatically inactivate protein synthesis. Pseudomonas exotoxin A ADP-ribosylates EF2, while ricin depurinates ribosomal RNA. Diphtheria-based toxins are internalized to endosomes where the A chain of the toxin translocates directly to the cytosol and ADP-ribosylates EF2. Cell death follows inhibition of protein synthesis. dgA: deglycosylated ricin A chain; EF2: elongation factor 2.