Recognition of Malondialdehyde-modified Proteins by the C Terminus of Complement Factor H Is Mediated via the Polyanion Binding Site and Impaired by Mutations Found in Atypical Hemolytic Uremic Syndrome

Hyvärinen, Satu; Uchida, Koji; Varjosalo, Markku; Jokela, Reija; Jokiranta, T. Sakari

doi:10.1074/jbc.m113.527416

Cited by 28 publications

(18 citation statements)

References 59 publications

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“…Several studies have examined the functional consequences of the 402 SNP in the context of full‐length FH, FHL‐1, the isolated CCP7 domain, or partial FH fragments entailing CCP6‐8. These studies have shown that the Y402H SNP results in modified binding to several ligands such as GAGs, C‐reactive protein, zinc ions, the extracellular matrix protein fibulin 3, and oxidation end‐products, with many of these findings generating controversy among the different reports. Remarkably, these studies have revealed that the differential binding properties of the Y402H variant are pronounced when the mutation is studied in the context of isolated, recombinant fragments of FH.…”

Section: Insights Into Fhl‐1 Functionmentioning

confidence: 99%

Protection of host cells by complement regulators

Schmidt

Lambris

Ricklin

2016

Immunological Reviews

177

168

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Summary The complement cascade is an ancient immune-surveillance system that not only provides protection from pathogen invasion but has also evolved to participate in physiological processes to maintain tissue homeostasis. The alternative pathway (AP) of complement activation is the evolutionarily oldest part of this innate immune cascade. It is unique in that it is continuously activated at a low level and arbitrarily probes foreign, modified-self, and also unaltered self-structures. This indiscriminate activation necessitates the presence of preformed regulators on autologous surfaces to spare self-cells from the undirected nature of AP activation. Although the other two canonical complement activation routes, the classical and lectin pathways, initiate the cascade more specifically through pattern recognition, their activity still needs to be tightly controlled to avoid excessive reactivity. It is the perpetual duty of complement regulators to protect the self from damage inflicted by inadequate complement activation. Here, we review the role of complement regulators as preformed mediators of defense, explain their common and specialized functions, and discuss selected cases in which alterations in complement regulators lead to disease. Finally, rational engineering approaches using natural complement inhibitors as potential therapeutics are highlighted.

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Section: Insights Into Fhl‐1 Functionmentioning

confidence: 99%

Protection of host cells by complement regulators

Schmidt

Lambris

Ricklin

2016

Immunological Reviews

177

168

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“…Additional ligands of FH include markers of oxidative stress, such as malondialdehyde (MDA) and malondialdehyde acetaldehyde (MAA) [121–123], and serum apolipoprotein E (ApoE) [124]. For example, FH is a major MDA-binding protein that interacts via CCPs 7 and 20 (see Fig.…”

Section: Other Ligands Of Factor Hmentioning

confidence: 99%

Complement factor H in host defense and immune evasion

Parente

Clark

Inforzato

et al. 2016

Cell. Mol. Life Sci.

152

147

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Complement is the major humoral component of the innate immune system. It recognizes pathogen- and damage-associated molecular patterns, and initiates the immune response in coordination with innate and adaptive immunity. When activated, the complement system unleashes powerful cytotoxic and inflammatory mechanisms, and thus its tight control is crucial to prevent damage to host tissues and allow restoration of immune homeostasis. Factor H is the major soluble inhibitor of complement, where its binding to self markers (i.e., particular glycan structures) prevents complement activation and amplification on host surfaces. Not surprisingly, mutations and polymorphisms that affect recognition of self by factor H are associated with diseases of complement dysregulation, such as age-related macular degeneration and atypical haemolytic uremic syndrome. In addition, pathogens (i.e., non-self) and cancer cells (i.e., altered-self) can hijack factor H to evade the immune response. Here we review recent (and not so recent) literature on the structure and function of factor H, including the emerging roles of this protein in the pathophysiology of infectious diseases and cancer.

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“…The assays that analyzed competition of FH binding by FH fragments were performed with 10 mM FH19-20 or 100 mM FH6-8. 29 To set up a calcein-release assay, HUVECs (3 3 10 6 in gelatin-PBS) were incubated with 25 mM calcein AM (BD Pharmingen) at 37°C for 30 minutes, followed by washing. Cells (1 3 10 4 ) were incubated with anti-CD59 antibody (0 to 0.13 mM) in 15% NHS for 15 minutes.…”

Section: Endothelial Cell Assaysmentioning

confidence: 99%

Disturbed sialic acid recognition on endothelial cells and platelets in complement attack causes atypical hemolytic uremic syndrome

Hyvärinen

Meri

Jokiranta

2016

Blood

Self Cite

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Key Points• Sialic acids are critical for factor H-mediated complement regulation on endothelial cells, erythrocytes, and platelets. • Impaired ability of factor H mutants to simultaneously bind sialic acid and C3b on cells explains their association with aHUS.Uncontrolled activation of the complement system against endothelial and blood cells is central to the pathogenesis of atypical hemolytic uremic syndrome (aHUS). aHUS patients frequently carry mutations in the inhibitory complement regulator factor H (FH). Mutations cluster in domains [19][20], which are critical for recognizing self surfaces. On endothelial cells, binding of FH is generally attributed to heparan sulfate. This theory, however, is questioned by the puzzling observation that some aHUSassociated mutations markedly enhance FH binding to heparin and endothelial cells. In this article, we show that, instead of disturbed heparin interactions, the impaired ability of C-terminal mutant FH molecules to recognize sialic acid in the context of surface-bound C3b explains their pathogenicity. By using recombinant FH19-20 as a competitor for FH and measuring erythrocyte lysis and deposition of complement C3b and C5b-9 on endothelial cells and platelets, we now show that several aHUS-associated mutations, which have been predicted to impair FH19-20 binding to sialic acid, prevent FH19-20 from antagonizing FH function on cells. When sialic acid was removed, the wild-type FH19-20 also lost its ability to interfere with FH function on cells. These results indicate that sialic acid is critical for FH-mediated complement regulation on erythrocytes, endothelial cells, and platelets. The inability of C-terminal mutant FH molecules to simultaneously bind sialic acid and C3b on cells provides a unifying explanation for their association with aHUS. Proper formation of FH-sialic acid-C3b complexes on surfaces exposed to plasma is essential for preventing cell damage and thrombogenesis characteristic of aHUS.

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Recognition of Malondialdehyde-modified Proteins by the C Terminus of Complement Factor H Is Mediated via the Polyanion Binding Site and Impaired by Mutations Found in Atypical Hemolytic Uremic Syndrome

Cited by 28 publications

References 59 publications

Protection of host cells by complement regulators

Protection of host cells by complement regulators

Complement factor H in host defense and immune evasion

Disturbed sialic acid recognition on endothelial cells and platelets in complement attack causes atypical hemolytic uremic syndrome

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