Factor H‐related protein 1: a complement regulatory protein and guardian of necrotic‐type surfaces

Skerka, Christine; Pradel, Gabriele; Halder, Luke D.; Zipfel, Peter F.; Zipfel, S.; Strauß, Olaf

doi:10.1111/bph.15290

Cited by 19 publications

(20 citation statements)

References 69 publications

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“…We demonstrated that FHR1, MFHR13 and the MFHR1 variants are able to bind not only to C5 and C5b6, but also to C6, C7, C8 and C9. The binding to C8 and C9 was significantly higher compared to C5b6, which suggest that regulation is not only mediated through C5b6-complex binding, as currently assumed (12). Our observations indicate an FHR1 activity resembling the function of vitronectin, which is a soluble regulator of the MAC (66), and thus contributes to the understanding of the mechanism of action of FHR1.…”

Section: Discussionsupporting

confidence: 50%

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A synthetic protein as efficient multitarget regulator against complement over-activation

Molina

Müeller

Hoernstein

et al. 2021

Preprint

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The complement system constitutes the innate defense against pathogens. Its dysregulation leads to diseases and is a critical determinant in many viral infections, e.g. COVID-19. Factor H (FH) is the main regulator of the alternative pathway of complement activation and could be a therapy to restore homeostasis. However, recombinant FH is not available. Engineered FH versions may be alternative therapeutics. Here, we designed a synthetic protein, MFHR13, as a multitarget complement regulator. It combines the dimerization and C5-regulatory domains of human FH-related protein 1 (FHR1) with the C3-regulatory and cell surface recognition domains of human FH, including SCR13. In summary, the fusion protein MFHR13 comprises SCRs FHR11-2:FH1-4:FH13:FH19-20. It protects sheep erythrocytes from complement attack exhibiting 26 and 4-fold the regulatory activity of eculizumab and human FH, respectively. Furthermore, we demonstrate that MFHR13 and FHR1 bind to all proteins forming the membrane attack complex, which contributes to the mechanistic understanding of FHR1. We consider MFHR13 a promising candidate as therapeutic for complement-associated diseases.

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Section: Discussionsupporting

confidence: 50%

“…The C-terminal region of FH (FH 19-20 ) is highly conserved in all FHRs, while none of them contains regions homologous to FH 1-4 (8). Of particular interest is FHR1, a regulator of C5 activation, which inhibits the last steps of the complement cascade (terminal pathway) and the MAC formation (10, 12).…”

Section: Introductionmentioning

confidence: 99%

A synthetic protein as efficient multitarget regulator against complement over-activation

Molina

Müeller

Hoernstein

et al. 2021

Preprint

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“…On human endothelial cells, C3b opsonization becomes more pronounced with increasing concentrations of FHR-1 and FHR-1(SV) ( Figure 6A), which impressively highlights the context-dependent role of FHR-1. Context dependent roles of FHR-1 have also been described in other reports for apoptotic and necrotic cells [reviewed in (50,51)]. Whether the observed inhibitory effect toward the C3 and the C5 convertases plays an important physiological role in vivo must be questioned for two reasons.…”

Section: Discussionmentioning

confidence: 75%

Deregulation of Factor H by Factor H-Related Protein 1 Depends on Sialylation of Host Surfaces

et al. 2021

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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.

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“…Interestingly plasma distributed regulators can also attach to surfaces. For example, both plasma regulators, Factor H and FHR1, bind to the glomerular basement membrane (Skerka et al 2020).…”

Section: C5bmentioning

confidence: 99%

Complement catalyzing glomerular diseases

et al. 2021

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Complement is an evolutionarily conserved system which is important in the defense against microorganisms and also in the elimination of modified or necrotic elements of the body. Complement is activated in a cascade type manner and activation and all steps of cascade progression are tightly controlled and regulatory interleaved with many processes of inflammatory machinery. Overshooting of the complement system due to dysregulation can result in the two prototypes of primary complement mediated renal diseases: C3 glomerulopathy and thrombotic microangiopathy. Apart from these, complement also is highly activated in many other inflammatory native kidney diseases, such as membranous nephropathy, ANCA-associated necrotizing glomerulonephritis, and IgA nephropathy. Moreover, it likely plays an important role also in the transplant setting, such as in antibody-mediated rejection or in hematopoietic stem cell transplant associated thrombotic microangiopathy. In this review, these glomerular disorders are discussed with regard to the role of complement in their pathogenesis. The consequential, respective clinical trials for complement inhibitory therapy strategies for these diseases are described.

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Factor H‐related protein 1: a complement regulatory protein and guardian of necrotic‐type surfaces

Cited by 19 publications

References 69 publications

A synthetic protein as efficient multitarget regulator against complement over-activation

A synthetic protein as efficient multitarget regulator against complement over-activation

Deregulation of Factor H by Factor H-Related Protein 1 Depends on Sialylation of Host Surfaces

Complement catalyzing glomerular diseases

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