A placenta-specific receptor for the fusogenic, endogenous retrovirus-derived, human syncytin-2
A placenta-specific receptor for the fusogenic, endogenous retrovirus-derived, human syncytin-2
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DOI：
10.1073/pnas.0807413105
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发表时间：
2008-11-11
影响因子：
11.1
通讯作者：
Heidmann, Thierry
中科院分区：
文献类型：
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作者：
Esnault, Cecile;Priet, Stephane;Heidmann, Thierry
合胞素-2是来自人类内源性逆转录病毒FRD（HERV-FRD）的包膜基因，其被祖先灵长类宿主吸收，在超过4000万年的进化中保守，在胎盘中特异性表达，并且具有可能有助于胎盘形态发生的细胞-细胞融合活性。在这里，我们使用GeneBridge 4人/中国仓鼠辐射杂交板，绘制并鉴定了合胞蛋白-2的人类受体。该受体-即主要易化因子超家族结构域包含2（MFSD 2）-属于具有10-12个跨膜结构域的假定碳水化合物转运蛋白大家族，位于染色体位置1p34.2，并且在进化中是保守的。MFSD 2的表达载体在转染合胞素-2时赋予否则不敏感的细胞融合性。它还赋予合胞素-2假型以感染性，这与该蛋白质是内源性逆转录病毒的祖先获得的HERV-FRD家族的受体一致。与人类基因不同的是，小鼠和大鼠MFSD 2都不能介导膜融合，这与啮齿动物在进化过程中所选择的哺乳动物来源的合胞素基因与人类合胞素基因不同源的事实一致。值得注意的是，MFSD 2在各种人类组织中的实时定量RT-PCR分析表明在胎盘中以及在人类BeWo绒毛膜癌细胞系中的特异性表达，其公开了在毛喉素诱导细胞-细胞融合和合胞体形成时受体表达的增强。使用MFSD 2特异性探针的人胎盘组织的原位杂交进一步明确地证明了在合体滋养层水平的受体表达再次与胎盘形态发生中的作用一致。
Syncytin-2 is an envelope gene from the human endogenous retrovirus FRD (HERV-FRD) co-opted by an ancestral primate host, conserved in evolution over >40 Myr, specifically expressed in the placenta, and with a cell-cell fusogenic activity likely contributing to placenta morphogenesis. Here, using the GeneBridge4 human/Chinese hamster radiation hybrid panel, we mapped and identified the human receptor for syncytin-2. This receptor-namely Major Facilitator Superfamily Domain Containing 2 (MFSD2)-belongs to a large family of presumptive carbohydrate transporters with 10-12 membrane-spanning domains, is located at chromosomal position 1p34.2, and is conserved in evolution. An expression vector for MFSD2 confers fusogenicity to otherwise insusceptible cells upon transfection of syncytin-2. it also confers infectivity to syncytin-2 pseudotypes, consistent with this protein being the receptor for the ancestrally acquired HERV-FRD family of endogenous retroviruses. At variance with the human gene, neither mouse nor rat MFSD2 can mediate membrane fusion, which is consistent with the fact that the envelope-derived syncytin genes co-opted by rodents during evolution are not orthologous to the human syncytin genes. Remarkably, a real-time quantitative RT-PCR analysis of MFSD2 in various human tissues demonstrates specific expression in the placenta, as well as in the human BeWo choriocarcinoma cell line, which discloses enhancement of receptor expression upon induction by forskolin of cell-cell fusion and syncytium formation. In situ hybridization of human placental tissue using an MFSD2-specific probe further unambiguously demonstrates receptor expression at the level of the syncytiotrophoblast again consistent with a role in placenta morphogenesis.