Ricin cytotoxicity is sensitive to recycling between the endoplasmic reticulum and the Golgi complex.
Cytotoxic proteins that kill mammalian cells by catalytically inhibiting protein synthesis must enter the cytosol in order to reach their substrates. With the exception of diphtheria toxin, which enters the cytosol from acidified endosomes, the intracellular site of translocation of other toxins including ricin, Escherichia coli Shiga-like toxin-1, and Pseudomonas exotoxin A is likely to involve early compartments of the secretory pathway. We have used a molecular approach to identify the site and mechanism of toxin delivery to the cytosol by transiently expressing mutant GTPases that inhibit the assembly of biochemical complexes mediating anterograde and retrograde transport in the exocytic and endocytic pathways. The results provide evidence to suggest that receptors actively recycling between the endoplasmic reticulum and terminal Golgi compartments are essential for toxin translocation to the cytosol from the endoplasmic reticulum. The rapid kinetics of intoxication demonstrate a substantial level of bidirectional membrane flow and sorting through the early secretory pathway.
Simpson
J C
JC
Department of Biological Sciences, University of Warwick, Coventry, United Kingdom.
Dascher
C
C
Roberts
L M
LM
Lord
J M
JM
Balch
W E
WE
D000595:Amino Acid Sequence; D001693:Biological Transport, Active; D016923:Cell Death / Q000187:drug effects; D004705:Endocytosis; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D005089:Exocytosis; D020558:GTP Phosphohydrolases / Q000235:genetics; D015870:Gene Expression; D006056:Golgi Apparatus / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D007700:Kinetics; D008562:Membrane Glycoproteins; D008969:Molecular Sequence Data; D009154:Mutation; D009842:Oligopeptides / Q000235:genetics; D021382:Protein Sorting Signals; D012276:Ricin / Q000493:pharmacokinetics* / Q000633:toxicity*; D014721:Vesicular stomatitis Indiana virus / Q000235:genetics; D014759:Viral Envelope Proteins / Q000235:genetics / Q000378:metabolism
C028391:G protein, vesicular stomatitis virus; D008562:Membrane Glycoproteins; D009842:Oligopeptides; D021382:Protein Sorting Signals; D014759:Viral Envelope Proteins; C073762:lysyl-aspartyl-glutamyl-leucine; D012276:Ricin; D020558:GTP Phosphohydrolases