Spider and bacterial sphingomyelinases D target cellular lysophosphatidic acid receptors by hydrolyzing lysophosphatidylcholine

J Biol Chem. 2004 Mar 19;279(12):10833-6. doi: 10.1074/jbc.C300563200. Epub 2004 Jan 19.

Abstract

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 ( approximately 20-40 microm) 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 LPA(1) 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Corynebacterium / enzymology*
  • Hydrolysis
  • Lysophosphatidylcholines / metabolism*
  • Phosphoric Diester Hydrolases / metabolism*
  • Receptors, G-Protein-Coupled / metabolism*
  • Receptors, Lysophosphatidic Acid
  • Recombinant Proteins / metabolism
  • Spiders

Substances

  • Lysophosphatidylcholines
  • Receptors, G-Protein-Coupled
  • Receptors, Lysophosphatidic Acid
  • Recombinant Proteins
  • Phosphoric Diester Hydrolases
  • sphingomyelin phosphodiesterase D