Title

Cellular internalization of cytolethal distending toxin: a new end to a known pathway

Authors

Authors

L. Guerra; K. Teter; B. N. Lilley; B. Stenerlow; R. K. Holmes; H. L. Ploegh; K. Sandvig; M. Thelestam;T. Frisan

Comments

Authors: contact us about adding a copy of your work at STARS@ucf.edu

Abbreviated Journal Title

Cell Microbiol.

Keywords

RETICULUM-ASSOCIATED DEGRADATION; DOUBLE-STRAND BREAKS; CHO-CELLS; RESISTANT; ENDOPLASMIC-RETICULUM; HAEMOPHILUS-DUCREYI; CHOLERA-TOXIN; BREFELDIN-A; CYCLE ARREST; BACTERIAL GENOTOXIN; GOLGI-COMPLEX; Cell Biology; Microbiology

Abstract

The cytolethal distending toxins (CDTs) are unique in their ability to induce DNA damage, activate checkpoint responses and cause cell cycle arrest or apoptosis in intoxicated cells. However, little is known about their cellular internalization pathway. We demonstrate that binding of the Haemophilus ducreyi CDT (HdCDT) on the plasma membrane of sensitive cells was abolished by cholesterol extraction with methyl-beta-cyclodextrin. The toxin was internalized via the Golgi complex, and retrogradely transported to the endoplasmic reticulum (ER), as assessed by N-linked glycosylation. Further translocation from the ER did not require the ER-associated degradation (ERAD) pathway, and was Derlin-1 independent. The genotoxic activity of HdCDT was dependent on its internalization and its DNase activity, as induction of DNA double-stranded breaks was prevented in Brefeldin A-treated cells and in cells exposed to a catalytically inactive toxin. Our data contribute to a better understanding of the CDT mode of action and highlight two important aspects of the biology of this bacterial toxin family: (i) HdCDT translocation from the ER to the nucleus does not involve the classical pathways followed by other retrogradely transported toxins and (ii) toxin internalization is crucial for execution of its genotoxic activity.

Journal Title

Cellular Microbiology

Volume

7

Issue/Number

7

Publication Date

1-1-2005

Document Type

Article

Language

English

First Page

921

Last Page

934

WOS Identifier

WOS:000229679900003

ISSN

1462-5814

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