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Deregulation of Factor H by Factor H-Related Protein 1 Depends on Sialylation of Host Surfaces
To discriminate between self and non-self surfaces and facilitate immune surveillance, the complement system relies on the interplay between surface-directed activators and regulators. The dimeric modulator FHR-1 is hypothesized to competitively remove the complement regulator FH from surfaces that...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7959842/ https://www.ncbi.nlm.nih.gov/pubmed/33732239 http://dx.doi.org/10.3389/fimmu.2021.615748 |
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author | Dopler, Arthur Stibitzky, Selina Hevey, Rachel Mannes, Marco Guariento, Mara Höchsmann, Britta Schrezenmeier, Hubert Ricklin, Daniel Schmidt, Christoph Q. |
author_facet | Dopler, Arthur Stibitzky, Selina Hevey, Rachel Mannes, Marco Guariento, Mara Höchsmann, Britta Schrezenmeier, Hubert Ricklin, Daniel Schmidt, Christoph Q. |
author_sort | Dopler, Arthur |
collection | PubMed |
description | To discriminate between self and non-self surfaces and facilitate immune surveillance, the complement system relies on the interplay between surface-directed activators and regulators. The dimeric modulator FHR-1 is hypothesized to competitively remove the complement regulator FH from surfaces that strongly fix opsonic C3b molecules—a process known as “deregulation.” The C-terminal regions of FH and FHR-1 provide the basis of this competition. They contain binding sites for C3b and host surface markers and are identical except for two substitutions: S1191L and V1197A (i.e., FH “SV”; FHR-1 “LA”). Intriguingly, an FHR-1 variant featuring the “SV” combination of FH predisposes to atypical hemolytic uremic syndrome (aHUS). The functional impact of these mutations on complement (de)regulation, and their pathophysiological consequences, have largely remained elusive. We have addressed these questions using recombinantly expressed wildtype, mutated, and truncated versions of FHR-1 and FH. The “SV” to “LA” substitutions did not affect glycosaminoglycan recognition and had only a small effect on C3b binding. In contrast, the two amino acids substantially affected the binding of FH and FHR-1 to α2,3-linked sialic acids as host surfaces markers, with the S-to-L substitution causing an almost complete loss of recognition. Even with sialic acid-binding constructs, notable deregulation was only detected on host and not foreign cells. The aHUS-associated “SV” mutation converts FHR-1 into a sialic acid binder which, supported by its dimeric nature, enables excessive FH deregulation and, thus, complement activation on host surfaces. While we also observed inhibitory activities of FHR-1 on C3 and C5 convertases, the high concentrations required render the physiological impact uncertain. In conclusion, the SV-to-LA substitution in the C-terminal regions of FH and FHR-1 diminishes its sialic acid-binding ability and results in an FHR-1 molecule that only moderately deregulates FH. Such FH deregulation by FHR-1 only occurs on host/host-like surfaces that recruit FH. Conversion of FHR-1 into a sialic acid binder potentiates the deregulatory capacity of FHR-1 and thus explains the pathophysiology of the aHUS-associated FHR-1 “SV” variant. |
format | Online Article Text |
id | pubmed-7959842 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-79598422021-03-16 Deregulation of Factor H by Factor H-Related Protein 1 Depends on Sialylation of Host Surfaces Dopler, Arthur Stibitzky, Selina Hevey, Rachel Mannes, Marco Guariento, Mara Höchsmann, Britta Schrezenmeier, Hubert Ricklin, Daniel Schmidt, Christoph Q. Front Immunol Immunology To discriminate between self and non-self surfaces and facilitate immune surveillance, the complement system relies on the interplay between surface-directed activators and regulators. The dimeric modulator FHR-1 is hypothesized to competitively remove the complement regulator FH from surfaces that strongly fix opsonic C3b molecules—a process known as “deregulation.” The C-terminal regions of FH and FHR-1 provide the basis of this competition. They contain binding sites for C3b and host surface markers and are identical except for two substitutions: S1191L and V1197A (i.e., FH “SV”; FHR-1 “LA”). Intriguingly, an FHR-1 variant featuring the “SV” combination of FH predisposes to atypical hemolytic uremic syndrome (aHUS). The functional impact of these mutations on complement (de)regulation, and their pathophysiological consequences, have largely remained elusive. We have addressed these questions using recombinantly expressed wildtype, mutated, and truncated versions of FHR-1 and FH. The “SV” to “LA” substitutions did not affect glycosaminoglycan recognition and had only a small effect on C3b binding. In contrast, the two amino acids substantially affected the binding of FH and FHR-1 to α2,3-linked sialic acids as host surfaces markers, with the S-to-L substitution causing an almost complete loss of recognition. Even with sialic acid-binding constructs, notable deregulation was only detected on host and not foreign cells. The aHUS-associated “SV” mutation converts FHR-1 into a sialic acid binder which, supported by its dimeric nature, enables excessive FH deregulation and, thus, complement activation on host surfaces. While we also observed inhibitory activities of FHR-1 on C3 and C5 convertases, the high concentrations required render the physiological impact uncertain. In conclusion, the SV-to-LA substitution in the C-terminal regions of FH and FHR-1 diminishes its sialic acid-binding ability and results in an FHR-1 molecule that only moderately deregulates FH. Such FH deregulation by FHR-1 only occurs on host/host-like surfaces that recruit FH. Conversion of FHR-1 into a sialic acid binder potentiates the deregulatory capacity of FHR-1 and thus explains the pathophysiology of the aHUS-associated FHR-1 “SV” variant. Frontiers Media S.A. 2021-02-25 /pmc/articles/PMC7959842/ /pubmed/33732239 http://dx.doi.org/10.3389/fimmu.2021.615748 Text en Copyright © 2021 Dopler, Stibitzky, Hevey, Mannes, Guariento, Höchsmann, Schrezenmeier, Ricklin and Schmidt http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Immunology Dopler, Arthur Stibitzky, Selina Hevey, Rachel Mannes, Marco Guariento, Mara Höchsmann, Britta Schrezenmeier, Hubert Ricklin, Daniel Schmidt, Christoph Q. Deregulation of Factor H by Factor H-Related Protein 1 Depends on Sialylation of Host Surfaces |
title | Deregulation of Factor H by Factor H-Related Protein 1 Depends on Sialylation of Host Surfaces |
title_full | Deregulation of Factor H by Factor H-Related Protein 1 Depends on Sialylation of Host Surfaces |
title_fullStr | Deregulation of Factor H by Factor H-Related Protein 1 Depends on Sialylation of Host Surfaces |
title_full_unstemmed | Deregulation of Factor H by Factor H-Related Protein 1 Depends on Sialylation of Host Surfaces |
title_short | Deregulation of Factor H by Factor H-Related Protein 1 Depends on Sialylation of Host Surfaces |
title_sort | deregulation of factor h by factor h-related protein 1 depends on sialylation of host surfaces |
topic | Immunology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7959842/ https://www.ncbi.nlm.nih.gov/pubmed/33732239 http://dx.doi.org/10.3389/fimmu.2021.615748 |
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