Gomez-Escobar N, Gregory W F, Maizels R M
Institute of Cell, Animal and Population Biology, University of Edinburgh, Edinburgh EH9 3JT, United Kingdom.
Infect Immun. 2000 Nov;68(11):6402-10. doi: 10.1128/IAI.68.11.6402-6410.2000.
A novel member of the transforming growth factor beta (TGF-beta) family has been identified in the filarial nematode parasite Brugia malayi by searching the recently developed Expressed Sequence Tag (EST) database produced by the Filarial Genome Project. Designated tgh-2, this new gene shows most similarity to a key product regulating dauer larva formation in Caenorhabditis elegans (DAF-7) and to the human down-modulatory cytokine TGF-beta. Homology to DAF-7 extends throughout the length of the 349-amino-acid (aa) protein, which is divided into an N-terminal 237 aa, including a putative signal sequence, a 4-aa basic cleavage site, and a 108-aa C-terminal active domain. Similarity to human TGF-beta is restricted to the C-terminal domain, over which there is a 32% identity between TGH-2 and TGF-beta1, including every cysteine residue. Expression of tgh-2 mRNA has been measured over the filarial life cycle. It is maximal in the microfilarial stage, with lower levels of activity around the time of molting within the mammal, but continues to be expressed by mature adult male and female parasites. Expression in both the microfilaria, which is in a state of arrested development, and the adult, which is terminally differentiated, indicates that tgh-2 may play a role other than purely developmental. This is consistent with our observation that TGH-2 is secreted by adult worms in vitro. Recombinant TGH-2 expressed in baculovirus shows a low level of binding to TGF-beta-receptor bearing mink lung epithelial cells (MELCs), which is partially inhibited (16 to 39%) with human TGF-beta, and activates plasminogen activator inhibitor-1 transcription in MELCs, a marker for TGF-beta-mediated transduction. Further tests will be required to establish whether the major role of B. malayi TGH-2 (Bm-TGH-2) is to modulate the host immune response via the TGF-beta pathway.
通过搜索由丝虫基因组计划产生的最新开发的表达序列标签（EST）数据库，在丝虫线虫寄生虫马来布鲁线虫中鉴定出一种转化生长因子β（TGF-β）家族的新成员。这个新基因被命名为tgh-2，它与秀丽隐杆线虫中调节 dauer 幼虫形成的关键产物（DAF-7）以及人类下调性细胞因子TGF-β最为相似。与DAF-7的同源性贯穿整个349个氨基酸（aa）的蛋白质长度，该蛋白质分为N端的237个aa，包括一个推定的信号序列、一个4个aa的碱性切割位点和一个108个aa的C端活性结构域。与人类TGF-β的相似性仅限于C端结构域，在该结构域上TGH-2与TGF-β1之间有32%的同一性，包括每个半胱氨酸残基。已在丝虫的整个生命周期中测量了tgh-2 mRNA的表达。它在微丝蚴阶段最高，在哺乳动物体内蜕皮时活性较低，但成熟的成年雌雄寄生虫仍继续表达。在处于发育停滞状态的微丝蚴和终末分化的成虫中都有表达，这表明tgh-2可能发挥除纯粹发育之外的其他作用。这与我们观察到的成虫在体外分泌TGH-2一致。在杆状病毒中表达的重组TGH-2与携带TGF-β受体的貂肺上皮细胞（MELCs）的结合水平较低，这被人类TGF-β部分抑制（16%至39%），并激活MELCs中的纤溶酶原激活物抑制剂-1转录，这是TGF-β介导的转导的一个标志物。需要进一步测试来确定马来布鲁线虫TGH-2（Bm-TGH-2）的主要作用是否是通过TGF-β途径调节宿主免疫反应。
