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J. Biol. Chem., Vol. 280, Issue 26, 25210-25215, July 1, 2005

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Accumulation of Diacylglycerol in the Chlamydia Inclusion Vacuole

POSSIBLE ROLE IN THE INHIBITION OF HOST CELL APOPTOSIS^*

From the Departments of ^aPediatrics and ^eCell Biology, ^bDivision of Rheumatology, The Hospital for Sick Children, and ^cInstitute of Medical Science, University of Toronto, Toronto M5G 1X8, Canada, ^hDepartment of Medicine, Division of Rheumatology, University Health Network, University of Toronto, Toronto M5T 2S8, Canada, ⁱMolecular Biology Program, the University of Colorado Health Sciences Center, ^jDepartment of Biochemistry and Cell Biology, National Institute of Infectious Diseases, Toyama, Shinjuku, Tokyo 162-0011, Japan, and ^fDepartment of Biochemistry, University of Toronto, Toronto M5S 1A8, Canada

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.

Received for publication, February 22, 2005 , and in revised form, April 18, 2005.

^* This study was supported by the Canadian Institutes of Health Research (CIHR), the Arthritis Society of Canada, the Arthritis Center of Excellence, and the Sanatorium Foundation. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^d Supported by CIHR fellowship, the Arthritis Society of Canada, and the Arthritis Center of Excellence.

^g Supported by a CIHR studentship.

^k The current holder of the Pitblado Chair in Cell Biology at The Hospital for Sick Children and Cross-appointed to the Department of Biochemistry, University of Toronto. To whom correspondence should be addressed: Dept. of Cell Biology, The Hospital for Sick Children, 555 University Ave., Toronto, Ontario M5G 1X8, Canada. Tel.: 416-813-5727; Fax: 416-813-5028; E-mail: sga{at}sickkids.ca.

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