Interaction of Shiga toxin 2 with complement regulators of the factor H protein family

• Published in: Molecular immunology Vol. 58; no. 1; pp. 77 - 84
• Main Authors: Poolpol, Kulwara, Orth-Höller, Dorothea, Speth, Cornelia, Zipfel, Peter F., Skerka, Christine, de Córdoba, Santiago Rodriguez, Brockmeyer, Jens, Bielaszewska, Martina, Würzner, Reinhard
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.03.2014
• Subjects: Amino Acid Sequence; Binding Sites; Blood Proteins - genetics; Blood Proteins - immunology; Complement C3b Inactivator Proteins - genetics; Complement C3b Inactivator Proteins - immunology; Complement Factor H - genetics; Complement Factor H - immunology; Complement regulatory proteins; Enterohemorrhagic Escherichia coli - pathogenicity; Escherichia coli; Escherichia coli Infections - immunology; Escherichia coli Infections - microbiology; Escherichia coli Infections - pathology; Factor H; Factor H-like protein 1; Factor H-related protein 1; Hemolytic uremic syndrome; Hemolytic-Uremic Syndrome - immunology; Hemolytic-Uremic Syndrome - microbiology; Hemolytic-Uremic Syndrome - pathology; Humans; Protein Binding - immunology; Shiga toxin; Shiga Toxin 2 - immunology; EHEC; FH; Factor H; FI; Shiga toxin; Hemolytic uremic syndrome; HUS; FHR-1; aHUS; Complement regulatory proteins; FHL-1; TCC; Stx; Factor H-like protein 1; SCRs; Factor H-related protein 1; MCP; hi-Stx; factor I; short consensus repeats; atypical HUS; membrane cofactor protein; enterohemorrhagic Escherichia coli; heat-inactivated Stx; terminal complement complex
• ISSN: 0161-5890; 1872-9142
• DOI: 10.1016/j.molimm.2013.11.009

•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.