Recruitment of BAD by the Chlamydia trachomatis Vacuole Correlates with Host-Cell Survival

Abstract

Chlamydiae replicate intracellularly in a vacuole called an inclusion. Chlamydial-infected host cells are protected from mitochondrion-dependent apoptosis, partly due to degradation of BH3-only proteins. The host-cell adapter protein 14-3-3β can interact with host-cell apoptotic signaling pathways in a phosphorylation-dependent manner. In Chlamydia trachomatis-infected cells, 14-3-3β co-localizes to the inclusion via direct interaction with a C. trachomatis-encoded inclusion membrane protein. We therefore explored the possibility that the phosphatidylinositol-3 kinase (PI3K) pathway may contribute to resistance of infected cells to apoptosis. We found that inhibition of PI3K renders C. trachomatis-infected cells sensitive to staurosporine-induced apoptosis, which is accompanied by mitochondrial cytochrome c release. 14-3-3β does not associate with the Chlamydia pneumoniae inclusion, and inhibition of PI3K does not affect protection against apoptosis of C. pneumoniae-infected cells. In C. trachomatis-infected cells, the PI3K pathway activates AKT/protein kinase B, which leads to maintenance of the pro-apoptotic protein BAD in a phosphorylated state. Phosphorylated BAD is sequestered via 14-3-3β to the inclusion, but it is released when PI3K is inhibited. Depletion of AKT through short-interfering RNA reverses the resistance to apoptosis of C. trachomatis-infected cells. BAD phosphorylation is not maintained and it is not recruited to the inclusion of Chlamydia muridarum, which protects poorly against apoptosis. Thus, sequestration of BAD away from mitochondria provides C. trachomatis with a mechanism to protect the host cell from apoptosis via the interaction of a C. trachomatis-encoded inclusion protein with a host-cell phosphoserine-binding protein.

A Legionella pneumophila -translocated substrate that is required for growth within macrophages and protection from host cell death

“…Although no proteins encoded by intracellular bac- teria that interfere with host cell death have been identified, there is ample evidence that such proteins must exist. For instance, cultured cells harboring replicating Chlamydia and Bartonella species are highly resistant to apoptosis-inducing agents (32)(33)(34)(35). In the case of Chlamydia, resistance to apoptosis seems to involve degradation of a variety of proapoptotic BH3-only domain proteins as well as sequestration of the proapoptotic Bid protein.…”

Chlamydial Intracellular Survival Strategies

“…In parallel, infection also leads to stabilization of IAP2 (inhibitor of apoptosis protein 2) and up-regulation of the prosurvival factor Mcl-1 (myeoloid cell leukemia) (Rajalingam et al 2006(Rajalingam et al , 2008Sharma et al 2011). Other mechanisms potentially include sequestration of Bad at the inclusion via 14-3-3b, and of protein kinase C-d (PKCd) through binding to diacylglycerol-enriched membranes in the vicinity of the inclusion (Scidmore and Hackstadt 2001;Tse et al 2005;Verbeke et al 2006). ) and blocking death-inducing signaling pathways presumably originating from the TNF family of receptors and cytokine receptors.…”

cPLA2 Regulates the Expression of Type I Interferons and Intracellular Immunity to Chlamydia trachomatis

“…Epithelial cells infected with Chlamydia display sustained activation of RAS and many of its downstream effectors including the PI3P-dependent kinase AKT and components of the MEK/ERK MAPK signaling module (5,13). The activation of both AKT and ERK enhance Chlamydia survival by protecting infected cells from apoptosis (4,13).…”

“…The activation of both AKT and ERK enhance Chlamydia survival by protecting infected cells from apoptosis (4,13). For example, ERK-depen-dent expression of Mcl-1 protects infected cells from apoptotic signal delivered by innate immune mediators early in infection (4).…”