Molecular bases for the association of FHR-1 with atypical hemolytic uremic syndrome and other diseases.

Autor:	Martin Merinero H; Centro de Investigaciones Biológicas Margarita Salas, Consejo Superior de Investigaciones Científicas, Madrid, Spain.; Centro de Investigacion Biomedica En Red de Enfermedades Raras, Madrid, Spain., Subías M; Centro de Investigaciones Biológicas Margarita Salas, Consejo Superior de Investigaciones Científicas, Madrid, Spain.; Centro de Investigacion Biomedica En Red de Enfermedades Raras, Madrid, Spain., Pereda A; Centro de Investigaciones Biológicas Margarita Salas, Consejo Superior de Investigaciones Científicas, Madrid, Spain., Gómez-Rubio E; Centro de Investigaciones Biológicas Margarita Salas, Consejo Superior de Investigaciones Científicas, Madrid, Spain., Juana Lopez L; Centro de Investigaciones Biológicas Margarita Salas, Consejo Superior de Investigaciones Científicas, Madrid, Spain.; Centro de Investigacion Biomedica En Red de Enfermedades Raras, Madrid, Spain., Fernandez C; Servicio de Nefrologia, Hospital Universitario A Coruña, A Coruña, Spain., Goicoechea de Jorge E; Department of Immunology, Complutense University and Research Institute Hospital 12 de Octubre (imas12), Madrid, Spain; and., Martin-Santamaria S; Centro de Investigaciones Biológicas Margarita Salas, Consejo Superior de Investigaciones Científicas, Madrid, Spain., Cañada FJ; Centro de Investigaciones Biológicas Margarita Salas, Consejo Superior de Investigaciones Científicas, Madrid, Spain.; Centro de Investigacion Biomedica En Red de Enfermedades Respiratorias, Madrid, Spain., Rodríguez de Córdoba S; Centro de Investigaciones Biológicas Margarita Salas, Consejo Superior de Investigaciones Científicas, Madrid, Spain.; Centro de Investigacion Biomedica En Red de Enfermedades Raras, Madrid, Spain.
Jazyk:	angličtina
Zdroj:	Blood [Blood] 2021 Jun 24; Vol. 137 (25), pp. 3484-3494.
DOI:	10.1182/blood.2020010069
Abstrakt:	Factor H (FH)-related proteins are a group of partly characterized complement proteins thought to promote complement activation by competing with FH in binding to surface-bound C3b. Among them, FH-related protein 1 (FHR-1) is remarkable because of its association with atypical hemolytic uremic syndrome (aHUS) and other important diseases. Using a combination of biochemical, immunological, nuclear magnetic resonance, and computational approaches, we characterized a series of FHR-1 mutants (including 2 associated with aHUS) and unraveled the molecular bases of the so-called deregulation activity of FHR-1. In contrast with FH, FHR-1 lacks the capacity to bind sialic acids, which prevents C3b-binding competition between FH and FHR-1 in host-cell surfaces. aHUS-associated FHR-1 mutants are pathogenic because they have acquired the capacity to bind sialic acids, which increases FHR-1 avidity for surface-bound C3-activated fragments and results in C3b-binding competition with FH. FHR-1 binds to native C3, in addition to C3b, iC3b, and C3dg. This unexpected finding suggests that the mechanism by which surface-bound FHR-1 promotes complement activation is the attraction of native C3 to the cell surface. Although C3b-binding competition with FH is limited to aHUS-associated mutants, all surface-bound FHR-1 promotes complement activation, which is delimited by the FHR-1/FH activity ratio. Our data indicate that FHR-1 deregulation activity is important to sustain complement activation and C3 deposition at complement-activating surfaces. They also support that abnormally elevated FHR-1/FH activity ratios would perpetuate pathological complement dysregulation at complement-activating surfaces, which may explain the association of FHR-1 quantitative variations with diseases. (© 2021 by The American Society of Hematology.)
Databáze:	MEDLINE
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