A newly identified Leishmania IF4E-interacting protein, Leish4E-IP2, modulates the activity of cap-binding protein paralogs.
A newly identified Leishmania IF4E-interacting protein, Leish4E-IP2, modulates the activity of cap-binding protein paralogs.
复制标题
新鉴定的利什曼原虫 IF4E 相互作用蛋白 Leish4E-IP2 可调节帽结合蛋白旁系同源物的活性。
DOI：
10.1093/nar/gkaa173
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发表时间：
2020
影响因子：
14.9
通讯作者：
Shapira,Michal
中科院分区：
文献类型：
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作者：
Tupperwar,Nitin;Meleppattu,Shimi;Shrivastava,Rohit;Baron,Nofar;Gilad,Ayelet;Wagner,Gerhard;Léger-Abraham,Mélissa;Shapira,Michal
真核生物中大多数细胞mRNAs的翻译都是通过帽依赖的途径进行的，由此帽结合复合体eIF4F将预起始复合体锚定在mRNAs的5‘端，并调节翻译起始。Leishmanito在不断变化的环境中生存的要求可以解释为什么它们编码多个eIF4E(LeishIF4E)和eIF4G(LeishIF4Gs)Paralog，因为每个都可以在其生命周期中被分配一个独立的角色。在这里，我们发现不同的LeishIF4E的表达和活性在培养的前鞭毛体的生长过程中发生了变化，这促使人们寻找调节蛋白。我们描述了一种新的LeishIF4E相互作用蛋白Leish4E-IP2，它含有一个保守的Y(X)4LΦIF4E结合基序。尽管Leish4E-IP2可以与多个LeishIF4E结合，但在m7GTP洗脱的帽子结合复合体中未检测到Leish4E-IP2，这表明它可以抑制LeishIF4E的帽子结合活性。通过功能实验，我们证明了重组形式的Leish4E-IP2抑制了LeishIF4E-1和LeishIF4E-3的帽子结合活性。此外，我们还表明，表达标记版本的Leish4E-IP2的转基因寄生虫也显示出测试的LeishIF4E的帽子结合活性降低，并减少了全局翻译。鉴于Leish4E-IP2可以与多个Leishif4E结合，我们认为Leish4E-IP2可以作为利什曼蛋白合成的广泛阻遏因子。
Translation of most cellular mRNAs in eukaryotes proceeds through a cap-dependent pathway, whereby the cap-binding complex, eIF4F, anchors the preinitiation complex at the 5′ end of mRNAs and regulates translation initiation. The requirement ofLeishmaniato survive in changing environments can explain why they encode multiple eIF4E (LeishIF4Es) and eIF4G (LeishIF4Gs) paralogs, as each could be assigned a discrete role during their life cycle. Here we show that the expression and activity of different LeishIF4Es change during the growth of cultured promastigotes, urging a search for regulatory proteins. We describe a novel LeishIF4E-interacting protein, Leish4E-IP2, which contains a conserved Y(X)4LΦ IF4E-binding-motif. Despite its capacity to bind several LeishIF4Es, Leish4E-IP2 was not detected in m7GTP-eluted cap-binding complexes, suggesting that it could inhibit the cap-binding activity of LeishIF4Es. Using a functional assay, we show that a recombinant form of Leish4E-IP2 inhibits the cap-binding activity of LeishIF4E-1 and LeishIF4E-3. Furthermore, we show that transgenic parasites expressing a tagged version of Leish4E-IP2 also display reduced cap-binding activities of tested LeishIF4Es, and decreased global translation. Given its ability to bind more than a single LeishIF4E, we suggest that Leish4E-IP2 could serve as a broad-range repressor ofLeishmaniaprotein synthesis.