Shiga toxin B subunits induce VWF secretion by human endothelial cells and thrombotic microangiopathy in ADAMTS13-deficient mice.

Abstract

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.

• Authors: Jing Huang, David G Motto, David R Bundle, J Evan Sadler
• Journal: Blood (Blood) Vol. 116 Issue 18 Pg. 3653-9 (Nov 04 2010) ISSN: 1528-0020 [Electronic] United States
• PMID: 20644116 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Caveolin 1
• Clathrin
• Shiga Toxins
• Trihexosylceramides
• stxB toxin
• von Willebrand Factor
• globotriaosylceramide
• Cholera Toxin
• Cholesterol
• ADAMTS13 protein, mouse
• Metalloendopeptidases
• ADAMTS13 Protein

Topics

• ADAMTS13 Protein
• Animals
• Caveolin 1 (genetics, metabolism)
• Cell Line
• Cholera Toxin (metabolism)
• Cholesterol (metabolism)
• Clathrin (metabolism)
• Endothelial Cells (metabolism)
• Gene Deletion
• Gene Knockdown Techniques
• Humans
• Metalloendopeptidases (genetics)
• Mice
• Mice, Inbred C57BL
• Shiga Toxins (adverse effects, metabolism)
• Shigella dysenteriae (metabolism)
• Thrombotic Microangiopathies (etiology, microbiology)
• Trihexosylceramides (metabolism)
• von Willebrand Factor (metabolism)