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J. Biol. Chem., Vol. 279, Issue 10, 9409-9416, March 5, 2004

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Activation of Raf/MEK/ERK/cPLA2 Signaling Pathway Is Essential for Chlamydial Acquisition of Host Glycerophospholipids^*

Heng Su, Grant McClarty, Feng Dong, Grant M. Hatch¶, Zhixing K. Pan||, and Guangming Zhong**

From the Department of Microbiology and Immunology, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229, Departments of Medical Microbiology and ^¶Pharmacology and Therapeutics, University of Manitoba, Winnipeg, Manitoba R3E OW3, Canada, and ^||Department of Microbiology and Immunology, Medical College of Ohio, Toledo, Ohio 43614

Chlamydiae, a diverse group of obligate intracellular pathogens replicating within cytoplasmic vacuoles of eukaryotic cells, are able to acquire lipids from host cells. Here we report that activation of the host Raf-MEK-ERK-cPLA2 signaling cascade is required for the chlamydial uptake of host glycerophospholipids. Both the MAP kinase pathway (Ras/Raf/MEK/ERK) and Ca²⁺-dependent cytosolic phospholipase A2 (cPLA2) were activated in chlamydia-infected cells. The inhibition of cPLA2 activity resulted in the blockade of the chlamydial uptake of host glycerophospholipids and impairment in chlamydial growth. Blocking either c-Raf-1 or MEK1/2 activity prevented the chlamydial activation of ERK1/2, leading to the suppression of both chlamydial activation of the host cPLA2 and uptake of glycerophospholipids from the host cells. The chlamydia-induced phosphorylation of cPLA2 was also blocked by a dominant negative ERK2. Furthermore, activation of both ERK1/2 and cPLA2 was dependent on chlamydial growth and restricted within chlamydia-infected cells, suggesting an active manipulation of the host ERK-cPLA2 signaling pathway by chlamydiae.

Received for publication, November 3, 2003 , and in revised form, December 3, 2003.

^* This work was supported in part by United States Department of Health Grants R01AI47997 and R01HL64883 (to G. Z.) and Canadian Institutes for Health Research Grant Gr-13301 (to G. M.). G. Z.'s and G. M.'s laboratories contributed equally to this work. 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.

^** To whom correspondence should be addressed: Dept. of Microbiology and Immunology, University of Texas Health Science Ctr. at San Antonio, 7703 Floyd Curl Dr., San Antonio, TX 78229. Tel.: 210-567-1169; Fax: 210-567-0293; E-mail: Zhongg{at}UTHSCSA.EDU.

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