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

Guerra, Lina (författare)
Teter, Ken (författare)
Lilley, Brendan N. (författare)
visa fler...
Stenerlöw, Bo (författare)
Uppsala universitet,Enheten för biomedicinsk strålningsvetenskap,BMS
Holmes, Randall K. (författare)
Ploegh, Hidde L. (författare)
Sandvig, Kirsten (författare)
Thelestam, Monica (författare)
Karolinska Institutet
Frisan, Teresa (författare)
Karolinska Institutet
visa färre...
 (creator_code:org_t)
2005-04-18
2005
Engelska.
Ingår i: Cellular Microbiology. - : Hindawi Limited. - 1462-5814 .- 1462-5822. ; 7:7, s. 921-34
  • Tidskriftsartikel (refereegranskat)
Abstract Ämnesord
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  • 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.

Nyckelord

Animals
Bacterial Toxins/*metabolism/toxicity
Binding Sites
Brefeldin A/pharmacology
Cell Line
Cell Membrane/*metabolism
Cholesterol/metabolism
Cytosol/metabolism
DNA/metabolism
Deoxyribonucleases
Endoplasmic Reticulum/*metabolism
Golgi Apparatus/*metabolism
Haemophilus ducreyi/*metabolism
Hela Cells
Humans
Magnesium/metabolism
Mice
Mutation
Protein Transport
Research Support; Non-U.S. Gov't
MEDICINE
MEDICIN

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