Accumulation of diacylglycerol in the Chlamydia inclusion vacuole: possible role in the inhibition of host cell apoptosis.
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 Cdelta (PKCdelta), a proapoptotic effector, to the immediate vicinity of the vacuole. PKCdelta normally exerts its pro-apoptotic effects at the mitochondria and in the nucleus. We speculate that Chlamydia antagonizes the pro-apoptotic effect of PKCdelta 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 PKCdelta 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.
Tse
Shirley M L
SM
Department of Pediatrics, Division of Rheumatology, The Hospital for Sick Children, University of Toronto, Toronto M5G 1X8, Canada.
Mason
David
D
Botelho
Roberto J
RJ
Chiu
Basil
B
Reyland
Mary
M
Hanada
Kentaro
K
Inman
Robert D
RD
Grinstein
Sergio
S
D000098:Acetophenones / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis; D001578:Benzopyrans / Q000494:pharmacology; D001665:Binding Sites; D020134:Catalytic Domain; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D002689:Chlamydia / Q000378:metabolism*; D002690:Chlamydia Infections / Q000378:metabolism; D006224:Cricetinae; D004075:Diglycerides / Q000737:chemistry*; D006367:HeLa Cells; D006801:Humans; D008055:Lipids / Q000737:chemistry; D008856:Microscopy, Fluorescence; D008928:Mitochondria / Q000378:metabolism; D010957:Plasmids / Q000378:metabolism; D011493:Protein Kinase C / Q000737:chemistry; D051745:Protein Kinase C-delta; D017434:Protein Structure, Tertiary; D013997:Time Factors; D014162:Transfection; D014617:Vacuoles / Q000378:metabolism*
D000098:Acetophenones; D001578:Benzopyrans; D004075:Diglycerides; D008055:Lipids; C085746:rottlerin; C497258:PRKCD protein, human; D011493:Protein Kinase C; D051745:Protein Kinase C-delta