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Infection and Immunity, December 2000, p. 6903-6911, Vol. 68, No. 12
Microbiology and Tumorbiology Center,
Karolinska Institutet, S-171 77 Stockholm,1 and
Department of Medical Microbiology and Immunology,
University of Gothenburg, S-413 46 Gothenburg,2
Sweden
Received 8 June 2000/Returned for modification 28 August
2000/Accepted 9 September 2000
The chancroid bacterium Haemophilus ducreyi produces a
toxin (HdCDT) which is a member of the recently discovered family of cytolethal distending toxins (CDTs). These protein toxins prevent the
cyclin-dependent kinase cdc2 from being activated, thus blocking the
transition of cells from the G2 phase into mitosis, with
the consequent arrest of intoxicated cells in G2. It is not
known whether these toxins act by signaling from the cell surface or intracellularly only. Here we report that HdCDT has to undergo at least
internalization before being able to act. Cellular intoxication was
inhibited (i) by removal of clathrin coats via K+
depletion, (ii) by treatment with drugs that inhibit receptor clustering into coated pits, and (iii) in cells genetically manipulated to fail in clathrin-dependent endocytosis. Intoxication was also completely inhibited in cells treated with bafilomycin A1 or nocodazole and in cells incubated at 18°C, i.e., under conditions known to block
the fusion of early endosomes with downstream
compartments. Moreover, disruption of the Golgi complex by treatment
with brefeldin A or ilimaquinone blocked intoxication.
In conclusion, our data indicate that HdCDT enters cells via
clathrin-coated pits and has to be transported via the Golgi
complex in order to intoxicate cells. This is the first member of
the family of CDTs for which cellular internalization and some details
of the pathway have been demonstrated.
0019-9567/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.
Cellular Internalization of Cytolethal Distending
Toxin from Haemophilus ducreyi
*
Corresponding author. Mailing address: Microbiology and
Tumorbiology Center (MTC), Karolinska Institutet, Box 280, S-171 77 Stockholm, Sweden. Phone: 46-8-728 71 62. Fax: 46-8-33 15 47. E-mail:
monica.thelestam{at}mtc.ki.se.
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