Placental syncytins: Genetic disjunction between the fusogenic and immunosuppressive activity of retroviral envelope proteins
Placental syncytins: Genetic disjunction between the fusogenic and immunosuppressive activity of retroviral envelope proteins
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DOI：
10.1073/pnas.0707873105
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发表时间：
2007-12-18
影响因子：
11.1
通讯作者：
Heidmann, Thierry
中科院分区：
文献类型：
--
作者：
Mangeney, Marianne;Renard, Martial;Heidmann, Thierry
我们之前已经证明，小鼠和灵长类逆转录病毒的包膜蛋白在体内具有免疫抑制作用。这种特性表现在，当蛋白质被通常被移植小鼠排斥的同种异体肿瘤细胞表达时，表达env的细胞能够逃脱(至少是暂时的)免疫排斥。在这里，我们分析了人和小鼠合胞素的免疫抑制活性。这些是内源性逆转录病毒的囊膜基因，由祖先宿主独立选择，在进化中保守，在胎盘中特异表达，具有细胞-细胞融合活性，可能有助于胎盘的形态发生。我们发现，在人类和小鼠中，两种合胞素中的一种(人合胞素-2和小鼠合胞素-B)具有免疫抑制作用，而另一种(人合胞素-1和小鼠合胞素-A)则不具有免疫抑制作用(尽管能够诱导细胞-细胞融合)。通过缺失分析描述免疫抑制结构域，结合免疫抑制和非免疫抑制序列的比较，我们可以推导出针对特定氨基酸的突变规则，导致从免疫抑制蛋白到非免疫抑制蛋白的选择性切换，反之亦然。这些结果揭开了逆转录病毒外膜的一个关键功能，在逆转录病毒内化过程中，外膜不一定是“单独”选择的，尽管在灵长类和小鼠科动物中，合胞素对在进化中“完全”保守。在不影响融合性的条件下，选择性地灭活免疫抑制，对于理解这一功能在胎盘生理学和母胎耐受中的作用应该是重要的。
We have previously demonstrated that the envelope proteins of a murine and primate retrovirus are immunosuppressive in vivo. This property was manifested by the ability of the proteins, when expressed by allogeneic tumor cells normally rejected by engrafted mice, to have the env-expressing cells escape (at least transiently) immune rejection. Here, we analyzed the immunosuppressive activity of the human and murine syncytins. These are envelope genes from endogenous retroviruses independently coopted by ancestral hosts, conserved in evolution, specifically expressed in the placenta, and with a cell-cell fusogenic activity likely contributing to placenta morphogenesis. We show that in both humans and mice, one of the two syncytins (human syncytin-2 and mouse syncytin-B) is immunosuppressive and, rather unexpectedly, the other (human syncytin-1 and mouse syncytin-A) is not (albeit able to induce cell-cell fusion). Delineation of the immunosuppressive domain by deletion analysis, combined with a comparison between immunosuppressive and nonimmunosuppressive sequences, allowed us to derive a mutation rule targeted to specific amino acids, resulting in selective switch from immunosuppressive to nonimmunosuppressive envelope proteins and vice versa. These results unravel a critical function of retroviral envelopes, not necessarily "individually" selected for in the retrovirus endogenization process, albeit "tandemly" conserved in evolution for the syncytin pairs in primates and Muridae. Selective inactivation of immunosuppression, under conditions not affecting fusogenicity, shou be important for understanding the role of this function in placental physiology and maternofetal tolerance.