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...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2021-02-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2021.615748/full |
| _version_ | 1818850021076893696 |
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| author | Arthur Dopler Selina Stibitzky Rachel Hevey Marco Mannes Mara Guariento Britta Höchsmann Britta Höchsmann Hubert Schrezenmeier Hubert Schrezenmeier Daniel Ricklin Christoph Q. Schmidt |
| author_facet | Arthur Dopler Selina Stibitzky Rachel Hevey Marco Mannes Mara Guariento Britta Höchsmann Britta Höchsmann Hubert Schrezenmeier Hubert Schrezenmeier Daniel Ricklin Christoph Q. Schmidt |
| author_sort | Arthur Dopler |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-12-19T06:42:30Z |
| format | Article |
| id | doaj.art-b93f354ac6754ce79b8066b0a202bbc6 |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-12-19T06:42:30Z |
| publishDate | 2021-02-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-b93f354ac6754ce79b8066b0a202bbc62022-12-21T20:32:01ZengFrontiers Media S.A.Frontiers in Immunology1664-32242021-02-011210.3389/fimmu.2021.615748615748Deregulation of Factor H by Factor H-Related Protein 1 Depends on Sialylation of Host SurfacesArthur Dopler0Selina Stibitzky1Rachel Hevey2Marco Mannes3Mara Guariento4Britta Höchsmann5Britta Höchsmann6Hubert Schrezenmeier7Hubert Schrezenmeier8Daniel Ricklin9Christoph Q. Schmidt10Institute of Pharmacology of Natural Products and Clinical Pharmacology, Ulm University, Ulm, GermanyInstitute of Pharmacology of Natural Products and Clinical Pharmacology, Ulm University, Ulm, GermanyDepartment of Pharmaceutical Sciences, University of Basel, Basel, SwitzerlandInstitute of Pharmacology of Natural Products and Clinical Pharmacology, Ulm University, Ulm, GermanyInstitute of Pharmacology of Natural Products and Clinical Pharmacology, Ulm University, Ulm, GermanyInstitute of Transfusion Medicine, University of Ulm, Ulm, GermanyInstitute of Clinical Transfusion Medicine and Immunogenetics Ulm, German Red Cross Blood Transfusion Service and University Hospital of Ulm, Ulm, GermanyInstitute of Transfusion Medicine, University of Ulm, Ulm, GermanyInstitute of Clinical Transfusion Medicine and Immunogenetics Ulm, German Red Cross Blood Transfusion Service and University Hospital of Ulm, Ulm, GermanyDepartment of Pharmaceutical Sciences, University of Basel, Basel, SwitzerlandInstitute of Pharmacology of Natural Products and Clinical Pharmacology, Ulm University, Ulm, GermanyTo 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.https://www.frontiersin.org/articles/10.3389/fimmu.2021.615748/fullcomplement systemfactor H related protein 1FHR-1factor H (FH)FH deregulationsialic acid |
| spellingShingle | Arthur Dopler Selina Stibitzky Rachel Hevey Marco Mannes Mara Guariento Britta Höchsmann Britta Höchsmann Hubert Schrezenmeier Hubert Schrezenmeier Daniel Ricklin Christoph Q. Schmidt Deregulation of Factor H by Factor H-Related Protein 1 Depends on Sialylation of Host Surfaces Frontiers in Immunology complement system factor H related protein 1 FHR-1 factor H (FH) FH deregulation sialic acid |
| 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 | complement system factor H related protein 1 FHR-1 factor H (FH) FH deregulation sialic acid |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2021.615748/full |
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