THE N-TERMINAL REGION OF THE 37-KDA TRANSLOCATED FRAGMENT OF PSEUDOMONAS EXOTOXIN-A ABORTS TRANSLOCATION BY PROMOTING ITS OWN EXPORT AFTER MICROSOMAL MEMBRANE INSERTION

The 37-kDa C-terminal fragment of Pseudomonas exotoxin A (PE; termed P E37 and composed of aa 280-613 of PE) translocates to the cell cytosol to cause cell death. PE37 requires a C-terminal endoplasmic reticulum retention sequence to be cytotoxic, indicating that the toxin may tra nslocate to the cytosol from the endoplasmic reticulum. We show here t hat the N-terminal region of nascent PE37 can be inserted into the mem brane of canine pancreatic microsomes by the preprocecropin signal seq uence but then is exported or released from microsomes. The 34 N-termi nal amino acids of the toxin fragment are sufficient to arrest translo cation and prevent the microsomal accumulation of nascent chains that otherwise are sequestered into microsomes. These data support a role f or the N-terminal region of PE37 in the translocation of the toxin fro m the endoplasmic reticulum to the cytosol in mammalian cells.