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

    Authors

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

    Comments

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    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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