A CD46-like Molecule Functional in Teleost Fish Represents an Ancestral Form of Membrane-Bound Regulators of Complement Activation
A CD46-like Molecule Functional in Teleost Fish Represents an Ancestral Form of Membrane-Bound Regulators of Complement Activation
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DOI：
10.4049/jimmunol.1303179
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发表时间：
2015-01
期刊：
影响因子：
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通讯作者：
Masakazu Tsujikura;Takahiro Nagasawa;Satoko Ichiki;Ryota Nakamura;T. Somamoto;M. Nakao
中科院分区：
文献类型：
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作者：
Masakazu Tsujikura;Takahiro Nagasawa;Satoko Ichiki;Ryota Nakamura;T. Somamoto;M. Nakao
在补体系统中，补体激活调节因子(RCA)在控制补体过度激活和保护宿主细胞免受补体的误导攻击方面起着至关重要的作用。一些RCA家族成员已经从环口和硬骨鱼中克隆出来，并被归类为可溶型和膜结合型，与哺乳动物RCA因子一样。补体调节功能仅被描述为七鳃鳗和条纹石斑鱼的可溶性RCA；然而，对于膜结合的RCA蛋白在低等脊椎动物中的生物学功能知之甚少。在本研究中，克隆了一个膜结合的RCA蛋白，命名为硬骨补体调节膜蛋白(Tecrem)，并对其补体调节作用进行了研究。Carp Tecrem是斑马鱼2型RCA，ZCR1的直系同源基因，与哺乳动物的CD46一样，它由四个短的共识重复模块组成，分别是一个丝氨酸/苏氨酸/脯氨酸富集区、一个跨膜区和一个细胞质结构域。Tecrem显示鲤鱼组织中普遍存在mRNA的表达，这与补体激活中假定的调节作用很好地一致。含鲤鱼TECREM的重组中国仓鼠卵巢细胞系对鲤鱼补体裂解活性的耐受性显著高于对照中国仓鼠卵巢细胞(模拟转染体)，而作用于靶细胞的主要C3亚型C3-S的沉积显著低于对照中国仓鼠卵巢细胞。抗Tecrem单抗可促进鲤鱼C3和两种C4亚型在自体红细胞上的沉积。因此，本研究结果提供了骨鱼补体被膜结合的第2类RCA调节的证据，暗示宿主细胞保护是补体系统调节中的一种进化保守机制。
In the complement system, the regulators of complement activation (RCA) play crucial roles in controlling excessive complement activation and in protecting host cell from misdirected attack of complement. Several members of RCA family have been cloned from cyclostome and bony fish species and classified into soluble and membrane-bound type as in mammalian RCA factors. Complement-regulatory functions have been described only for soluble RCA of lamprey and barred sand bass; however, little is known on the biological function of the membrane-bound RCA proteins in the lower vertebrates. In this study, a membrane-bound RCA protein, designated teleost complement-regulatory membrane protein (Tecrem), was cloned and characterized for its complement-regulatory roles. Carp Tecrem, an ortholog of a zebrafish type 2 RCA, ZCR1, consists of four short consensus repeat modules, a serine/threonine/proline-rich domain, a transmembrane region, and a cytoplasmic domain, from the N terminus, as does mammalian CD46. Tecrem showed a ubiquitous mRNA expression in carp tissues, agreeing well with the putative regulatory role in complement activation. A recombinant Chinese hamster ovary cell line bearing carp Tecrem showed a significantly higher tolerance against lytic activity of carp complement and less deposition of C3-S, the major C3 isotypes acting on the target cell, than control Chinese hamster ovary (mock transfectant). Anti-Tecrem mAb enhanced the depositions of carp C3 and two C4 isotypes on autologous erythrocytes. Thus, the present findings provide the evidence of complement regulation by a membrane-bound group 2 RCA in bony fish, implying the host–cell protection is an evolutionarily conserved mechanism in regulation of the complement system.