Spider and bacterial sphingomyelinases D target cellular lysophosphatidic acid receptors by hydrolyzing lysophosphatidylcholine.
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.
van Meeteren
Laurens A
LA
Division of Cellular Biochemistry and Centre for Biomedical Genetics, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
Frederiks
Floor
F
Giepmans
Ben N G
BN
Pedrosa
Matheus F Fernandes
MF
Billington
Stephen J
SJ
Jost
B Helen
BH
Tambourgi
Denise V
DV
Moolenaar
Wouter H
WH
D000818:Animals; D003352:Corynebacterium / Q000201:enzymology*; D006868:Hydrolysis; D008244:Lysophosphatidylcholines / Q000378:metabolism*; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D049368:Receptors, Lysophosphatidic Acid; D011994:Recombinant Proteins / Q000378:metabolism; D013112:Spiders
D008244:Lysophosphatidylcholines; D043562:Receptors, G-Protein-Coupled; D049368:Receptors, Lysophosphatidic Acid; D011994:Recombinant Proteins; D010727:Phosphoric Diester Hydrolases; C055160:sphingomyelin phosphodiesterase D