Journal
BLOOD
Volume 137, Issue 25, Pages 3484-3494Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/blood.2020010069
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Funding
- Spanish Ministerio de Economia y Competitividad-FEDER grants [SAF2015-66287-R, PID2019-104912RB-I00, RTI2018-094751-B-C22, CTQ2017-88353-R]
- Autonomous Region of Madrid [S2017/BMD-3673]
- Spanish Ministerio de Ciencia, Innovacion y Universidades-FEDER grants [RYC-2013-13395, RTI2018-095955-B-100]
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Factor H (FH)-related protein 1 (FHR-1) plays a significant role in diseases like atypical hemolytic uremic syndrome (aHUS) by competing with FH in binding to surface-bound C3b to promote complement activation. Abnormally elevated FHR-1/FH activity ratios perpetuate pathological complement dysregulation at complement-activating surfaces.
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.
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