Chlamydia infection depends on a functional MDM2-p53 axis.
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.
Department of Molecular Biology, Max Planck Institute for Infection Biology, Charitéplatz 1, 10117 Berlin, Germany.
Erik
E
González
1] Department of Molecular Biology, Max Planck Institute for Infection Biology, Charitéplatz 1, 10117 Berlin, Germany [2] Steinbeis Innovation Center for Systems Biomedicine, Falkensee, Germany.
Marion
M
Rother
1] Department of Molecular Biology, Max Planck Institute for Infection Biology, Charitéplatz 1, 10117 Berlin, Germany [2] Institute for Molecular Bioscience, University of Queensland, St Lucia, Queensland 4072, Australia.
Markus C
MC
Kerr
Department of Molecular Biology, Max Planck Institute for Infection Biology, Charitéplatz 1, 10117 Berlin, Germany.
Munir A
MA
Al-Zeer
Department of Molecular Biology, Max Planck Institute for Infection Biology, Charitéplatz 1, 10117 Berlin, Germany.
Mohammad
M
Abu-Lubad
Department of Molecular Biology, Max Planck Institute for Infection Biology, Charitéplatz 1, 10117 Berlin, Germany.
Mirjana
M
Kessler
Department of Molecular Biology, Max Planck Institute for Infection Biology, Charitéplatz 1, 10117 Berlin, Germany.
Volker
V
Brinkmann
Berlin Institute for Medical Systems Biology, Max-Delbrück-Center for Molecular Medicine, Robert-Rössle-Strasse 10, 13125 Berlin, Germany.
Alexander
A
Loewer
Department of Molecular Biology, Max Planck Institute for Infection Biology, Charitéplatz 1, 10117 Berlin, Germany.
Thomas F
TF
Meyer
D017209:Apoptosis / Q000502:physiology; D015153:Blotting, Western; D002471:Cell Transformation, Neoplastic / Q000378:metabolism; D002689:Chlamydia / Q000472:pathogenicity / Q000502:physiology; D002690:Chlamydia Infections / Q000378:metabolism* / Q000503:physiopathology; D002692:Chlamydia trachomatis / Q000472:pathogenicity* / Q000502:physiology; D006367:HeLa Cells / Q000382:microbiology; D006801:Humans; D010766:Phosphorylation; D051736:Proto-Oncogene Proteins c-mdm2 / Q000502:physiology*; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*
D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2