PRELP Protein Inhibits the Formation of the Complement Membrane Attack Complex
PRELP Protein Inhibits the Formation of the Complement Membrane Attack Complex
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DOI：
10.1074/jbc.m111.291476
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发表时间：
2012-03-09
影响因子：
4.8
通讯作者：
Blom, Anna M.
中科院分区：
文献类型：
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作者：
Happonen, Kaisa E.;Furst, Camilla Melin;Blom, Anna M.
PRELP是在多种细胞外基质中发现的58-kDa蛋白聚糖，包括软骨和几种基底膜。在类风湿性关节炎（RA）中，软骨组织被破坏，并且片段化的分子（包括PRELP）被释放到滑液中，在滑液中它们可以与补体系统的组分相互作用。在先前的研究中，发现PRELP与补体抑制剂C4 b结合蛋白相互作用，这被认为是在RA期间局部下调关节中的补体激活。在这里，我们表明，PRELP通过结合C9直接抑制补体的所有途径，从而防止膜攻击复合物（MAC）的形成。PRELP不干扰C9和已经形成的C5 b-8之间的相互作用，但抑制C9聚合，从而防止形成溶解孔。此外，由于PRELP和C3之间的相互作用，旁路途径已经在C3转化酶形成的水平上被抑制。这表明PRELP可能下调补体对基底膜和受损软骨的攻击，因此限制了炎症性疾病如RA中的病理性补体激活。PRELP介导的补体抑制的净结果将高度依赖于其他补体调节分子的局部浓度以及可用补体蛋白的局部浓度。
PRELP is a 58-kDa proteoglycan found in a variety of extracellular matrices, including cartilage and at several basement membranes. In rheumatoid arthritis (RA), the cartilage tissue is destroyed and fragmented molecules, including PRELP, are released into the synovial fluid where they may interact with components of the complement system. In a previous study, PRELP was found to interact with the complement inhibitor C4b-binding protein, which was suggested to locally down-regulate complement activation in joints during RA. Here we show that PRELP directly inhibits all pathways of complement by binding C9 and thereby prevents the formation of the membrane attack complex (MAC). PRELP does not interfere with the interaction between C9 and already formed C5b-8, but inhibits C9 polymerization thereby preventing formation of the lytic pore. The alternative pathway is moreover inhibited already at the level of C3-convertase formation due to an interaction between PRELP and C3. This suggests that PRELP may down-regulate complement attack at basement membranes and on damaged cartilage and therefore limit pathological complement activation in inflammatory disease such as RA. The net outcome of PRELP-mediated complement inhibition will highly depend on the local concentration of other complement modulating molecules as well as on the local concentration of available complement proteins.