Endocytosis, Intracellular Transport, and Cytotoxic Action of Shiga Toxin
and Ricin.
SANDVIG, KIRSTEN AND BO VAN DEURS.
Institute for Cancer Research, The Norwegian Radium Hospital, Montebello,
Oslo, Norway; and Structural Cell Biology Unit, Department of Medical Anatomy,
The Panum Institute, University of Copenhagen, Copenhagen, Denmark
APStracts 2:0032P, 1996.
ABSTRACT
Protein toxins such as ricin and Shiga toxin with intracellular targets have
to be endocytosed and translocated to the cytosol to inhibit the protein
synthesis and thereby kill the cell. Ricin is internalized by both clathrin-
dependent and -independent endocytic mechanisms, whereas Shiga toxin seems to
be taken up exclusively from clathrin-coated pits. After endocytosis,
internalized membrane and content are delivered to endosomes, where sorting
for further routing in the cell takes place. Toxins that remain membrane bound
at low endosomal pH can be recycled to the cell surface or transcytosed in
polarized epithelia. A large proportion of internalized toxin is transported
to lysosomes for degradation. Most importantly, a fraction of the internalized
ricin and Shiga toxin molecules is delivered to the [i]trans[r]-Golgi network
(TGN). Shiga toxin can, in some very sensitive cells, be transported
retrogradely through the Golgi cisterns all the way back to the endoplasmic
reticulum (ER), and it is possible that also ricin is transported retrogradely
to the ER. In this review, a cell biological overview of these intracellular
transport steps is presented, and evidence is provided that the delivery to
the TGN and the subsequent retrograde transport to the ER are required for
optimal intoxication. Moreover, it is argued that knowledge of this transport
is important for targeted drug delivery such as the application of
immunotoxins in cancer therapy.
APS Manuscript Number P14-6.
Article publication pending October 1996, Physiological Reviews.
ISSN 1080-4757 Copyright 1996 The American Physiological Society.
Published in APStracts on 13 November 1996