Chlamydia trachomatis plasmid-encoded protein Pgp3 inhibits apoptosis via the PI3K-AKT-mediated MDM2-p53 axis

Abstract

Chlamydia trachomatis, the most common human pathogen that causes trachoma and sexually transmitted disease, has developed various strategies for inhibiting host cell apoptosis. Activation of the PI3K (phosphoinositide 3-kinase)/AKT-mediated MDM2 (murine double minute 2)-p53 pathway plays a prominent role in the apoptosis resistance arising from C. trachomatis infection. However, the precise upstream mechanisms by which C. trachomatis activates this pathway have not been adequately investigated. Here, we reveal that the secreted C. trachomatis plasmid-encoded protein Pgp3 inhibits apoptosis in HeLa cells. This process requires the activation of the PI3K/AKT signaling pathway, thereby leading to phosphorylation and nuclear entry of MDM2, and p53 degradation. PI3 K inhibitor LY294002 and MDM2 inhibitor Nutlin-3a block Pgp3-induced inhibition of HeLa cell apoptosis, suggesting a critical role for the PI3K/AKT pathway and its effect on the MDM2-p53 axis in Pgp3 anti-apoptotic activity.

Long Non-Coding RNA BC040587 is Required in Cell Invasion of Renal Cancer Induced by Acidosis

“…ERK phosphorylated Mdm2 at Ser166 in liver cancer [26], while activation of the PI3K-AKT pathway phosphorylates of MDM2 [27]. Likely, Activation of ERK and AKT leads to phosphorylation of MDM2 in RCC (Fig.…”

Nitroxoline induces cell apoptosis by inducing MDM2 degradation in small‐cell lung cancer

“…Proto‐oncogene MDM2 promotes tumorigenesis by targeting tumor suppressor proteins, such as p53, for proteasomal degradation . In this study, a panel of SCLC cell lines was treated with 20 μM NXQ for 24 hours, followed by immunoblotting assay (Figure A).…”

“…Proto-oncogene MDM2 promotes tumorigenesis by targeting tumor suppressor proteins, such as p53, for proteasomal degradation. 11 In this study, a panel of SCLC cell lines was treated with 20 μM NXQ for 24 hours, followed by immunoblotting assay ( Figure 3A). And the results showed that NXQ significantly downregulated the protein level of MDM2, along with p53 upregulation F I G U R E 2 Nitroxoline (NXQ) induces cell apoptosis in small-cell lung cancer (SCLC) cells.…”

The Nature and Extent of Plasmid Variation in Chlamydia trachomatis

“…C. trachomatis Pgp3 neutralizes the antichlamydial activity of human cathelicidin LL-37 [29] and is essential for colonisation of the gastrointestinal tract [30] due to evasion of acidic barriers (in both stomach and vagina) [31]. Pgp3 expression is also shown to inhibit apoptosis via the PI3K-AKT-mediated MDM2-p53 axis [32]. Table 1.…”

“…The gene product of CDS5, Pgp3, is the only plasmid-encoded protein secreted into the inclusion lumen and cytosol [23]. Pgp3 may be important in host cell invasion [21], and has recently been identified as being an inhibitor of apoptosis in cell culture, via activation of the PI3K/AKT signalling pathway [32]. This interaction of Pgp3 with host cell signalling pathways suggests that CDS5 may be subject to immune selection, and the accumulation of LGV-specific nonsynonymous SNPs in this gene may suggest a role in LGV tropism, a notion supported by the five-fold higher expression of Pgp-3 in LGV compared to ocular strains [8].…”