Shiga toxin B subunits induce VWF secretion by human endothelial cells and thrombotic microangiopathy in ADAMTS13-deficient mice.
Diarrhea-associated hemolytic uremic syndrome (D+HUS) is the most common cause of acute renal failure among children. Renal damage in D+HUS is caused by Shiga toxin (Stx), which is elaborated by Shigella dysenteriae and certain strains of Escherichia coli, in North America principally E coli O157:H7. Recent studies demonstrate that Stx also induces von Willebrand factor (VWF) secretion by human endothelial cells and causes thrombotic thrombocytopenic purpura, a disease with similarities to D+HUS, in Adamts13(-/-) mice. Stx occurs in 2 variants, Stx1 and Stx2, each of which is composed of 1 catalytically active A subunit that is responsible for cytotoxicity, and 5 identical B subunits that mediate binding to cell-surface globo-triaosylceramide. We now report that B subunits from Stx1 or Stx2 can stimulate the acute secretion of VWF in the absence of the cytotoxic A subunit. This rapid effect requires binding and clustering of globotriaosylceramide, and depends on plasma membrane cholesterol and caveolin-1 but not clathrin. Furthermore, similar to Stx2 holotoxin, the isolated Stx2B subunits induce thrombotic microangiopathy in Adamts13(-/-) mice. These results demonstrate the existence of a novel Stx B-induced lipid raft-dependent signaling pathway in endothelial cells that may be responsible for some of the biological effects attributed previously to the cytotoxic Stx A subunit.
Huang
Jing
J
Departments of Medicine, Biochemistry, and Molecular Biophysics, Washington University School of Medicine, St Louis, MO 63110, USA.
Motto
David G
DG
Bundle
David R
DR
Sadler
J Evan
JE
D000071120:ADAMTS13 Protein; D000818:Animals; D051242:Caveolin 1 / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D002772:Cholera Toxin / Q000378:metabolism; D002784:Cholesterol / Q000378:metabolism; D002966:Clathrin / Q000378:metabolism; D042783:Endothelial Cells / Q000378:metabolism*; D017353:Gene Deletion; D055785:Gene Knockdown Techniques; D006801:Humans; D008666:Metalloendopeptidases / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D022603:Shiga Toxins / Q000009:adverse effects* / Q000378:metabolism*; D012762:Shigella dysenteriae / Q000378:metabolism*; D057049:Thrombotic Microangiopathies / Q000209:etiology* / Q000382:microbiology; D014281:Trihexosylceramides / Q000378:metabolism; D014841:von Willebrand Factor / Q000378:metabolism*
D051242:Caveolin 1; D002966:Clathrin; D022603:Shiga Toxins; D014281:Trihexosylceramides; C077239:stxB toxin; D014841:von Willebrand Factor; C018549:globotriaosylceramide; D002772:Cholera Toxin; D002784:Cholesterol; C502939:ADAMTS13 protein, mouse; D008666:Metalloendopeptidases; D000071120:ADAMTS13 Protein