Chlamydia infection depends on a functional MDM2-p53 axis

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.

Expansion of the Chlamydia trachomatis inclusion does not require bacterial replication

“…Cml blocked both bacterial replication and inclusion expansion ( Fig. 2A-C), suggesting that protein synthesis is required for chlamydial inclusion expansion, corroborating a recent observation (Gonzalez et al, 2014). Together, these data suggest that the C. trachomatis inclusion can expand in the absence of bacterial replication.…”

Human and Pathogen Factors Associated with Chlamydia trachomatis-Related Infertility in Women

“…They demonstrated that sustained p53 downregulation is the key event that prevents apoptosis in Chlamydia-infected cells and that this is actively mediated by Chlamydia via the p53-MDM2 axis and ubiquitination (76,77). These important in vitro findings demonstrate that it is not just via innate immune and pathogen defense pathways that Chlamydia impacts the cell, but other central host cell pathways are also fundamentally required for the pathogen's survival.…”

“…Recently, two teams demonstrated important links among apoptosis, cell survival, and carcinogenesis for Chlamydia (76,77). They demonstrated that sustained p53 downregulation is the key event that prevents apoptosis in Chlamydia-infected cells and that this is actively mediated by Chlamydia via the p53-MDM2 axis and ubiquitination (76,77).…”

Subversion of Cell-Autonomous Host Defense by Chlamydia Infection

“…Eradication of p53 was shown to depend on PI3K/AKT signaling and HDM2-mediated p53 ubiquitination and proteasomal degradation. Gonzalez et al showed that p53 depletion is, at least to some extent, important for chlamydial apoptosis resistance (Gonzalez et al 2014). Moreover, Siegl and co-workers described an additional role of p53 during Chlamydia infection related to the host cell metabolism.…”

“…Dependent on the degree of damage, p53 also induces apoptosis by the stimulation of Bax and Bak oligomerization as well as increased gene expression of multiple pro-apoptotic proteins such as Bax, Puma, or Noxa (Siegl and Rudel 2015). Chlamydia actively deplete p53 levels during infection and enriched p53 levels in the cell interfere with chlamydial inclusion formation and replication (Siegl et al 2014;Gonzalez et al 2014). Eradication of p53 was shown to depend on PI3K/AKT signaling and HDM2-mediated p53 ubiquitination and proteasomal degradation.…”