Factor H-related protein 1 (CFHR-1) inhibits complement C5 convertase activity and terminal complex formation
Factor H-related protein 1 (CFHR-1) inhibits complement C5 convertase activity and terminal complex formation
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DOI：
10.1182/blood-2009-02-205641
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发表时间：
2009-09-17
期刊：
影响因子：
20.3
通讯作者：
Skerka, Christine
中科院分区：
文献类型：
--
作者：
Heinen, Stefan;Hartmann, Andrea;Skerka, Christine
人类1号染色体中包含CFHR 1和CFHR 3基因的84 kb基因组片段的纯合缺失代表溶血性尿毒症综合征（HUS）的风险因素，但对年龄相关性黄斑变性（AMD）具有保护作用。在这里，我们确定CFHR 1作为一种新的补体途径的抑制剂，阻断C5转化酶的活性和干扰C5 b表面沉积和MAC的形成。这种活性与补体因子H不同，并且显然因子H和CFHR 1以顺序方式控制补体激活。由于两种蛋白质都结合到细胞表面的相同或相似位点，因此CFHR 1活性的获得可能是以CFH介导的功能（抑制C3转化酶）为代价的。在HUS中，CFHR 1的缺乏可能导致对末端复合物形成的抑制减少，以及在补体攻击时对内皮细胞的保护减少。这些发现为细胞表面和生物表面的补体调节提供了新的见解，并可能定义CFHR 1在人类疾病中的作用。（血。2009; 114：2439-2447）
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. (Blood. 2009; 114: 2439-2447)