Interaction of Shiga toxin 2 with complement regulators of the factor H protein family
•Role of complement regulatory proteins in the pathogenesis of Stx-associated HUS.•Shiga toxin 2 (Stx2) binds to the factor H (FH) family proteins FHR-1 and FHL-1.•FHR-1 binds to Stx2 via its C-terminal region (SCRs 3–5).•FHR-1 competes with FH for Stx2 binding leading to reduced cofactor activity o...
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Published in | Molecular immunology Vol. 58; no. 1; pp. 77 - 84 |
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Main Authors | , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
England
Elsevier Ltd
01.03.2014
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Subjects | |
Online Access | Get full text |
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Summary: | •Role of complement regulatory proteins in the pathogenesis of Stx-associated HUS.•Shiga toxin 2 (Stx2) binds to the factor H (FH) family proteins FHR-1 and FHL-1.•FHR-1 binds to Stx2 via its C-terminal region (SCRs 3–5).•FHR-1 competes with FH for Stx2 binding leading to reduced cofactor activity of FH.•FHL-1 retains its cofactor activity in the fluid phase when bound to Stx2.
Shiga toxin 2 (Stx2) is believed to be a major virulence factor of enterohemorrhagic Escherichia coli (EHEC) contributing to hemolytic uremic syndrome (HUS). The complement system has recently been found to be involved in the pathogenesis of EHEC-associated HUS. Stx2 was shown to activate complement via the alternative pathway, to bind factor H (FH) at short consensus repeats (SCRs) 6–8 and 18–20 and to delay and reduce FH cofactor activity on the cell surface.
We now show that complement factor H-related protein 1 (FHR-1) and factor H-like protein 1 (FHL-1), proteins of the FH protein family that show amino acid sequence and regulatory function similarities with FH, also bind to Stx2. The FHR-1 binding site for Stx2 was located at SCRs 3–5 and the binding capacity of FHR-1*A allotype was higher than that of FHR-1*B. FHR-1 and FHL-1 competed with FH for Stx2 binding, and in the case of FHR-1 this competition resulted in a reduction of FH cofactor activity. FHL-1 retained its cofactor activity in the fluid phase when bound to Stx2.
In conclusion, multiple interactions of key complement inhibitors FH, FHR-1 and FHL-1 with Stx2 corroborate our hypothesis of a direct role of complement in EHEC-associated HUS. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 ObjectType-Article-2 ObjectType-Feature-1 |
ISSN: | 0161-5890 1872-9142 |
DOI: | 10.1016/j.molimm.2013.11.009 |