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The bacterial porin OmpA is an inhibitor of Bak-activation at mitochondria and blocks apoptosis of human cells infected with Chlamydia trachomatis

ABSTRACT: Many infectious agents have the need to inhibit host apoptosis, and various strategies are known. Chlamydia trachomatis is an obligate intracellular bacterium replicating in a vacuole in the human cytosol. Chlamydia-infected human cells are strongly protected against apoptosis. We here mapped this anti-apoptotic activity to the direct blockade of the effectors of mitochondrial apoptosis, the Bcl-2-family proteins Bax and Bak. Molecular analysis of Bak revealed the inhibition of activation-associated conformational changes by the infection. Surprisingly, we identified the C. trachomatis outer membrane porin OmpA in a complex with Bak on mitochondria. When expressed in uninfected human cells, OmpA was imported into mitochondrial membranes. OmpA alone blocked apoptosis and reproduced the changes to Bak-activation observed during infection, reminiscent of the established activity of the human mitochondrial porin, VDAC2. The results suggest that C. trachomatis utilizes the relationship between gram-negative bacteria and mitochondria to block apoptosis and to secure its intracellular growth.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Oliver Schilling

LAB HEAD: Prof. Dr. Oliver Schilling

PROVIDER: PXD011848 | Pride | 2026-01-26

REPOSITORIES: Pride

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Chlamydial membrane vesicles deliver the beta barrel membrane protein OmpA to mitochondria to inhibit apoptosis

Project description:Chlamydiae are obligate intracellular bacteria that inhibit mitochondrial apoptosis to maintain integrity of the host cell. We have previously reported that a chlamydial outer membrane b-barrel protein, OmpA, can during ectopic expression inhibit mitochondrial apoptosis through direct interaction with the BCL-2-family effectors BAX and BAK. We here show that OmpA from Chlamydia trachomatis (Ctr) uses membrane vesicles for its delivery to the outer mitochondrial membrane during Ctr infection. Using a number of imaging and fractionation techniques, we show that OmpA during infection reaches mitochondria and is inserted into mitochondrial membranes. Chlamydia derived vesicles (CDV) from Ctr-infected cells contained OmpA as well as other outer membrane proteins and LPS. When added to uninfected cells, CDVs fused with mitochondrial membranes, causing the interaction of OmpA with BAK and the cytosolic retro-translocation of BAX. CDV addition to uninfected cells also protected the cells against apoptosis. We previously showed tha OmpA works in co-ordination with VDAC2 to block apoptosis and here propose a structural model of this BAK inhibition by OmpA that reenacts the inhibition of BAK by VDAC2. The results provide evidence that OmpA from Chlamydia, as well as the structurally similar ortholog from the related Simkania, specifically exploits its relationship to mitochondrial porins to protect the infected cell against apoptosis and to enable intracellular growth of the bacteria in human cells.

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Project description:Certain types of Human papilloma viruses (HPV) are the etiological agents for cervical cancer. However, not all infections of high-risk HPVs will finally lead to cancer since most HPV infections are cleared without any consequences. Chlamydia trachomatis is the most prevalent sexual transmitted bacteria and is an obligatory intracellular pathogen exhibiting tropism in endocervical epithelial cells. Over the past decades, C. trachomatis is thought to be a potential co-factor for cervical cancer formation, but there are also studies that did not show such a correlation. To address this question in molecular terms, we stably expressed HPV16 E6 and E7 in spontaneously immortalized NOKs (normal oral keratinocytes) and performed SILAC (stable isotope labeling by amino acids in cell culture) with or without C. trachomatis infection to study the impact of HPV16 oncogene expression and C. trachomatis infection on host proteome changes.

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