Tumor Suppressor p53 Alters Host Cell Metabolism to Limit Chlamydia trachomatis Infection

• Published in: Cell reports (Cambridge) Vol. 9; no. 3; pp. 918 - 929
• Main Authors: Siegl, Christine, Prusty, Bhupesh K., Karunakaran, Karthika, Wischhusen, Jörg, Rudel, Thomas
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 06.11.2014; Elsevier
• Subjects: Animals; Cell Death; Chlamydia Infections - metabolism; Chlamydia Infections - microbiology; Chlamydia Infections - pathology; Chlamydia trachomatis - physiology; DNA Repair; Down-Regulation; Fibroblasts - metabolism; Fibroblasts - microbiology; Glucosephosphate Dehydrogenase - metabolism; Glycolysis; Host-Pathogen Interactions; Human Umbilical Vein Endothelial Cells - metabolism; Human Umbilical Vein Endothelial Cells - microbiology; Human Umbilical Vein Endothelial Cells - ultrastructure; Humans; Mice; Phosphatidylinositol 3-Kinases - metabolism; Protein Stability; Proto-Oncogene Proteins c-mdm2 - metabolism; Tumor Suppressor Protein p53 - metabolism
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2014.10.004

Obligate intracellular bacteria depend entirely on nutrients from the host cell for their reproduction. Here, we show that obligate intracellular Chlamydia downregulate the central tumor suppressor p53 in human cells. This reduction of p53 levels is mediated by the PI3K-Akt signaling pathway, activation of HDM2, and subsequent proteasomal degradation of p53. The stabilization of p53 in human cells severely impaired chlamydial development and caused the loss of infectious particle formation. DNA-damage-induced p53 interfered with chlamydial development through downregulation of the pentose phosphate pathway (PPP). Increased expression of the PPP key enzyme glucose-6-phosphate dehydrogenase rescued the inhibition of chlamydial growth induced by DNA damage or stabilized p53. Thus, downregulation of p53 is a key event in the chlamydial life cycle that reprograms the host cell to create a metabolic environment supportive of chlamydial growth. [Display omitted] •Chlamydia induces degradation of the tumor suppressor p53•Stabilization of p53 severely impairs chlamydial development•Degradation of p53 unleashes the pentose phosphate pathway for metabolic support•G6PD expression overcomes the DNA damage response and rescues chlamydial growth Nutrient supply from the host cell is essential for the survival of obligate intracellular bacteria. The tumor suppressor p53 plays a crucial role in host cell metabolism. Siegl et al. now highlight the role of p53 in host cell defense during infection by Chlamydia and show how this pathogen counteracts p53 for survival.