title: Factor H-related protein 1 (CFHR-1) inhibits complement C5 convertase activity and terminal complex formation.
abstract: Homozygous deletion of a 84-kb genomic fragment in human chromosome 1 that encompasses the CFHR1 and CFHR3 genes represents a risk factor for hemolytic uremic syndrome (HUS) but has a protective effect in age-related macular degeneration (AMD). Here we identify CFHR1 as a novel inhibitor of the complement pathway that blocks C5 convertase activity and interferes with C5b surface deposition and MAC formation. This activity is distinct from complement factor H, and apparently factor H and CFHR1 control complement activation in a sequential manner. As both proteins bind to the same or similar sites at the cellular surfaces, the gain of CFHR1 activity presumably is at the expense of CFH-mediated function (inhibition of the C3 convertase). In HUS, the absence of CFHR1 may result in reduced inhibition of terminal complex formation and in reduced protection of endothelial cells upon complement attack. These findings provide new insights into complement regulation on the cell surface and biosurfaces and likely define the role of CFHR1 in human diseases.
authors.affiliation: Department of Infection Biology, Leibniz Institute for Natural Product Research and Infection Biology, Hans Knöll Institute, Jena, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Heinen
authors.forename: Andrea
authors.initials: A
authors.lastname: Hartmann
authors.forename: Nadine
authors.initials: N
authors.lastname: Lauer
authors.forename: Ulrike
authors.initials: U
authors.lastname: Wiehl
authors.forename: Hans-Martin
authors.initials: HM
authors.lastname: Dahse
authors.forename: Sylvia
authors.initials: S
authors.lastname: Schirmer
authors.forename: Katharina
authors.initials: K
authors.lastname: Gropp
authors.forename: Tina
authors.initials: T
authors.lastname: Enghardt
authors.forename: Reinhard
authors.initials: R
authors.lastname: Wallich
authors.forename: Steffi
authors.initials: S
authors.lastname: Hälbich
authors.forename: Michael
authors.initials: M
authors.lastname: Mihlan
authors.forename: Ursula
authors.initials: U
authors.lastname: Schlötzer-Schrehardt
authors.forename: Peter F
authors.initials: PF
authors.lastname: Zipfel
authors.forename: Christine
authors.initials: C
authors.lastname: Skerka
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D050577:Complement C3-C5 Convertases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D003179:Complement C3b / Q000378:metabolism; D003180:Complement C3b Inactivator Proteins / Q000502:physiology*; D015933:Complement C3d / Q000378:metabolism; D017242:Complement Factor H / Q000378:metabolism; D015938:Complement Membrane Attack Complex / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D004912:Erythrocytes / Q000378:metabolism; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D006801:Humans; D007124:Immunoenzyme Techniques; D047468:Immunoprecipitation; D007668:Kidney / Q000166:cytology / Q000378:metabolism; D018613:Microscopy, Confocal; D012160:Retina / Q000166:cytology / Q000378:metabolism; D012756:Sheep; D014471:Umbilical Veins / Q000166:cytology / Q000378:metabolism
chemical_list: C493495:CFH protein, human; C517621:CFHR1 protein, human; D003180:Complement C3b Inactivator Proteins; D015938:Complement Membrane Attack Complex; D003179:Complement C3b; D015933:Complement C3d; D017242:Complement Factor H; D050577:Complement C3-C5 Convertases