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Chlamydia infection depends on a functional MDM2-p53 axis.

González, Erik and Rother, Marion and Kerr, Markus C. and Al-Zeer, Munir A. and Abu-Lubad, Mohammad and Kessler, Mirjana and Brinkmann, Volker and Loewer, Alexander and Meyer, Thomas F. (2014):
Chlamydia infection depends on a functional MDM2-p53 axis.
In: Nature communications, p. 5201, 5, ISSN 2041-1723, [Article]

Abstract

Chlamydia, a major human bacterial pathogen, assumes effective strategies to protect infected cells against death-inducing stimuli, thereby ensuring completion of its developmental cycle. Paired with its capacity to cause extensive host DNA damage, this poses a potential risk of malignant transformation, consistent with circumstantial epidemiological evidence. Here we reveal a dramatic depletion of p53, a tumor suppressor deregulated in many cancers, during Chlamydia infection. Using biochemical approaches and live imaging of individual cells, we demonstrate that p53 diminution requires phosphorylation of Murine Double Minute 2 (MDM2; a ubiquitin ligase) and subsequent interaction of phospho-MDM2 with p53 before induced proteasomal degradation. Strikingly, inhibition of the p53-MDM2 interaction is sufficient to disrupt intracellular development of Chlamydia and interferes with the pathogen's anti-apoptotic effect on host cells. This highlights the dependency of the pathogen on a functional MDM2-p53 axis and lends support to a potentially pro-carcinogenic effect of chlamydial infection.

Item Type: Article
Erschienen: 2014
Creators: González, Erik and Rother, Marion and Kerr, Markus C. and Al-Zeer, Munir A. and Abu-Lubad, Mohammad and Kessler, Mirjana and Brinkmann, Volker and Loewer, Alexander and Meyer, Thomas F.
Title: Chlamydia infection depends on a functional MDM2-p53 axis.
Language: English
Abstract:

Chlamydia, a major human bacterial pathogen, assumes effective strategies to protect infected cells against death-inducing stimuli, thereby ensuring completion of its developmental cycle. Paired with its capacity to cause extensive host DNA damage, this poses a potential risk of malignant transformation, consistent with circumstantial epidemiological evidence. Here we reveal a dramatic depletion of p53, a tumor suppressor deregulated in many cancers, during Chlamydia infection. Using biochemical approaches and live imaging of individual cells, we demonstrate that p53 diminution requires phosphorylation of Murine Double Minute 2 (MDM2; a ubiquitin ligase) and subsequent interaction of phospho-MDM2 with p53 before induced proteasomal degradation. Strikingly, inhibition of the p53-MDM2 interaction is sufficient to disrupt intracellular development of Chlamydia and interferes with the pathogen's anti-apoptotic effect on host cells. This highlights the dependency of the pathogen on a functional MDM2-p53 axis and lends support to a potentially pro-carcinogenic effect of chlamydial infection.

Journal or Publication Title: Nature communications
Volume: 5
Divisions: 10 Department of Biology
10 Department of Biology > Systems Biology of the Stress Response
Date Deposited: 02 Sep 2015 08:27
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