Molecular bases for the association of FHR-1 with atypical hemolytic uremic syndrome and other diseases.
Molecular bases for the association of FHR-1 with atypical hemolytic uremic syndrome and other diseases.
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DOI：
10.1182/blood.2020010069
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发表时间：
2021-06-24
期刊：
影响因子：
20.3
通讯作者：
Rodríguez de Córdoba S
中科院分区：
文献类型：
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作者：
Martin Merinero H;Subías M;Pereda A;Gómez-Rubio E;Juana Lopez L;Fernandez C;Goicoechea de Jorge E;Martin-Santamaria S;Cañada FJ;Rodríguez de Córdoba S
Martin Merineo等人描述了突变因子H相关蛋白1(FHR-1)与非典型溶血性尿毒症综合征(AHUS)相关的分子基础，并阐明了调节补体激活的因子H(CFH)和FHR-1之间的相互作用。CFH有一个与细胞结合的C-末端结构域和一个促进活化补体降解的N-末端结构域。FHR-1缺乏补体降解活性，与细胞膜结合能力差；罕见的突变增加了细胞表面的结合，增加了补体C3的募集，导致补体活化和aHU增加。AHUS相关的FHR-1突变体是致病的，因为它们获得了结合唾液酸的能力，这允许C3b与FH结合竞争。表面结合的FHR-1促进补体激活的机制是天然C3与细胞表面的结合和吸引。因子H(FH)相关蛋白是一组部分特征的补体蛋白，被认为通过与FH竞争结合表面结合C3b来促进补体激活。其中，FH相关蛋白1(FHR-1)因其与非典型溶血性尿毒症综合征(AHUS)等重要疾病的相关性而备受关注。结合生化、免疫学、核磁共振和计算方法，我们鉴定了一系列FHR-1突变体(包括2个与aHUS相关的突变体)，并揭示了FHR-1所谓的去调控活性的分子基础。与FH相比，FHR-1缺乏与唾液酸结合的能力，这阻止了FH与FHR-1在宿主细胞表面的C3b结合竞争。AHUS相关的FHR-1突变体是致病的，因为它们获得了结合唾液酸的能力，这增加了FHR-1对表面结合的C3激活片段的亲和力，并导致C3b与FH的结合竞争。FHR-1除了与C3b、iC3b和C3dg结合外，还与本地C3结合。这一意想不到的发现表明，表面结合的FHR-1促进补体激活的机制是天然C3对细胞表面的吸引。虽然C3b与FH的结合竞争仅限于aHUS相关的突变体，但所有表面结合的FHR-1都促进补体激活，这由FHR-1/FH活性比率来界定。我们的数据表明，FHR-1的去调节活性对于维持补体激活和补体激活表面的C3沉积是重要的。他们还支持异常升高的FHR-1/FH活性比率将使补体激活表面的病理性补体失调持续存在，这可能解释了FHR-1数量变化与疾病的关联。
Martin Merinero et al delineate the molecular basis for association of mutant factor H–related protein 1 (FHR-1) with atypical hemolytic uremic syndrome (aHUS) and elucidate the interactions between factor H (CFH) and FHR-1 that regulate complement activation. CFH has a C-terminal domain that binds to cells and an N-terminal domain that facilitates degradation of activated complement. FHR-1 lacks complement-degrading activity and binds poorly to cell membranes; rare mutations allow increased cell surface binding and increase recruitment of complement C3, leading to increases in complement activation and aHUS. aHUS-associated FHR-1 mutants are pathogenic because they acquire capacity to bind sialic acids, which allows C3b-binding competition with FH. The mechanism by which surface-bound FHR-1 promotes complement activation is the binding and attraction of native C3 to the cell surface. 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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DOI：
10.4049/jimmunol.0804031
发表时间：
2009-06-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Ferreira VP;Herbert AP;Cortés C;McKee KA;Blaum BS;Esswein ST;Uhrín D;Barlow PN;Pangburn MK;Kavanagh D
通讯作者：
Kavanagh D
影响因子：
13.6
作者：
de Jorge, Elena Goicoechea;Tortajada, Agustin;de Cordoba, Santiago Rodriguez
通讯作者：
de Cordoba, Santiago Rodriguez
影响因子：
15.9
作者：
Tortajada, Agustin;Yebenes, Hugo;Rodriguez de Cordoba, Santiago
通讯作者：
Rodriguez de Cordoba, Santiago
影响因子：
8.6
作者：
Närkiö-Mäkelä, M;Hellwage, J;Meri, S
通讯作者：
Meri, S
影响因子：
4.3
作者：
Schmidt CQ;Hipgrave Ederveen AL;Harder MJ;Wuhrer M;Stehle T;Blaum BS
通讯作者：
Blaum BS