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J. Biol. Chem., Vol. 279, Issue 12, 10833-10836, March 19, 2004

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ACCELERATED PUBLICATIONS

Spider and Bacterial Sphingomyelinases D Target Cellular Lysophosphatidic Acid Receptors by Hydrolyzing Lysophosphatidylcholine^*

Laurens A. van Meeteren, Floor Frederiks, Ben N. G. Giepmans, Matheus F. Fernandes Pedrosa, Stephen J. Billington, B. Helen Jost, Denise V. Tambourgi, and Wouter H. Moolenaar¶

From the Division of Cellular Biochemistry and Centre for Biomedical Genetics, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands, the Laboratório de Imunoquímica, Instituto Butantan, 05503-900 São Paulo, S.P., Brazil, and the Department of Veterinary Science and Microbiology, University of Arizona, Tucson, Arizona 85721

Bites by Loxosceles spiders can produce severe clinical symptoms, including dermonecrosis, thrombosis, vascular leakage, hemolysis, and persistent inflammation. The causative factor is a sphingomyelinase D (SMaseD) that cleaves sphingomyelin into choline and ceramide 1-phosphate. A similar enzyme, showing comparable bioactivity, is secreted by certain pathogenic corynebacteria and acts as a potent virulence factor. However, the molecular basis for SMaseD toxicity is not well understood, which hampers effective therapy. Here we show that the spider and bacterial SMases D hydrolyze albumin-bound lysophosphatidylcholine (LPC), but not sphingosylphosphorylcholine, with K_m values (20–40 µM) well below the normal LPC levels in blood. Thus, toxic SMases D have intrinsic lysophospholipase D activity toward LPC. LPC hydrolysis yields the lipid mediator lysophosphatidic acid (LPA), a known inducer of platelet aggregation, endothelial hyperpermeability, and pro-inflammatory responses. Introduction of LPA₁ receptor cDNA into LPA receptor-negative cells renders non-susceptible cells susceptible to SmaseD, but only in LPC-containing media. Degradation of circulating LPC to LPA with consequent activation of LPA receptors may have a previously unappreciated role in the pathophysiology of secreted SMases D.

Received for publication, December 29, 2003 , and in revised form, January 16, 2004.

^* This work was supported by the Dutch Cancer Society. 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.

The on-line version of this article (available at http://www.jbc.org) contains Supplemental Figs. 1 and 2.

^¶ To whom correspondence should be addressed: Division of Cellular Biochemistry, The Netherlands Cancer Inst., Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands. Tel.: 31-20-5121971; Fax: 31-20-5121989; E-mail: w.moolenaar{at}nki.nl.

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