Accumulation of Diacylglycerol in the Chlamydia Inclusion Vacuole

Abstract

Intracellular pathogens have developed strategies to survive for extended periods inside their host cells. These include avoidance of host microbicidal effectors, often by sequestration in a protected subcompartment of the host cell. In some cases, the parasites exert also an antiapoptotic effect that prolongs the life of the infected host cell. Chlamydia utilizes both strategies, but the underlying molecular mechanisms are incompletely understood. Comparatively, little is known regarding the effects that Chlamydia exerts on the metabolism and distribution of the host cell lipids. The expression of fluorescently tagged C1 domains revealed that diacylglycerol is greatly accumulated in the immediate vicinity of Chlamydia inclusion vacuoles. The concentrated diacylglycerol recruits protein kinase C␦ (PKC␦), a proapoptotic effector, to the immediate vicinity of the vacuole. PKC␦ normally exerts its pro-apoptotic effects at the mitochondria and in the nucleus. We speculate that Chlamydia antagonizes the pro-apoptotic effect of PKC␦ by sequestering the enzyme on the inclusion vacuole away from its conventional target sites. Accordingly, we found that the ectopic expression of a catalytic fragment of PKC␦ that cannot be recruited by the vacuole, because it lacks a functional C1 domain, overcame the anti-apoptotic effect of the bacteria. The scavenging of pro-apoptotic factors may provide a novel mechanism whereby pathogens promote their own survival by extending the life of the host cells they infect.

Eukaryotic Protein Recruitment into the Chlamydia Inclusion: Implications for Survival and Growth

“…We propose that sequestration of ZNF23 into the Ct inclusion is another example of the bacterial-induced blockade mechanism of host cell-death [20], [31]–[36]. Our results establish that, in addition to host-derived lipids and lipid bodies, lipid metabolic enzymes of the host cell are also recruited into the inclusion.…”

Tarp regulates earlyChlamydia-induced host cell survival through interactions with the human adaptor protein SHC1

“…Alternatively, recent studies have implicated the anti-apoptotic BCL-2 family member MCL-1 as a key factor in preventing apoptosis (Rajalingam et al, 2008). In addition, Chlamydia subverts the function of the pro-apoptotic PKC by increasing diacylglycerol levels in the chlamydial inclusion membrane (Tse et al, 2005). Together, these observations suggest that Chlamydia prevents host cell apoptosis through a variety of mechanisms, likely acting sequentially as infection proceeds (Fan et al, 1998;Perfettini et al, 2002;Rajalingam et al, 2008).…”

Tetanus Toxin Hc Fragment Induces the Formation of Ceramide Platforms and Protects Neuronal Cells against Oxidative Stress

“…Thus, and taking into account that a moderate increase in ceramide levels leads to promotion of neuron survival [10], the observation of the increase ceramide by Hc-TeTx gains insight into part of the Hc-driven signaling mechanism used in the promotion of neuron resistance to stress. A mechanism leading to the same end is described for Chlamydia, which inhibits host cell apoptosis by accumulation of diacylglycerol in the inclusion vacuole and subsequent sequestering of PKCδ [53]. PKCδ is the member of the PKC family with the greatest number of described isoenzymes, generated by alternative splicing (from I to VIII), comprising either anti and proapoptotic isoforms [54].…”