Initially identified as a factor involved in tyrosine kinase receptor signaling, Grb10-interacting GYF protein 2 (GIGYF2) has later been shown to interact with the 5′ cap-binding protein 4EHP as part of a translation repression complex, and to mediate post-transcriptional repression of tethered reporter mRNAs. A current model proposes that GIGYF2 is indirectly recruited to mRNAs by specific RNA-binding proteins (RBPs) leading to translation repression through its association with 4EHP. Accordingly, we recently observed that GIGYF2 also interacts with the miRNA-induced silencing complex and probably modulates its translation repression activity. Here we have further investigated how GIGYF2 represses mRNA function. In a tethering reporter assay, we identify three independent domains of GIGYF2 with repressive activity. In this assay, GIGYF2-mediated repression is independent of 4EHP but largely dependent on the CCR4/NOT complex that GIGYF2 recruits through multiple interfaces. Importantly, we show that GIGYF2 is an RBP and identify for the first time endogenous mRNA targets that recapitulate 4EHP-independent repression. Altogether, we propose that GIGYF2 has two distinct mechanisms of repression: one depends on 4EHP binding and mainly affects translation; the other is 4EHP-independent and involves the CCR4/NOT complex and its deadenylation activity.

中文翻译：

---

RNA结合蛋白GIGYF2对内源性mRNA的4EHP依赖性抑制

最初被确定为酪氨酸激酶受体信号转导的因素，Grb10相互作用的GYF蛋白2（GIGYF2）后来被证明与5'帽结合蛋白4EHP相互作用，作为翻译抑制复合物的一部分，并介导转录后转录抑制束缚的记者mRNA。当前的模型提出，GIGYF2通过特定的RNA结合蛋白（RBP）间接募集到mRNA，从而通过与4EHP结合而导致翻译抑制。因此，我们最近观察到，GIGYF2也与miRNA诱导的沉默复合物相互作用，并可能调节其翻译抑制活性。在这里，我们进一步研究了GIGYF2如何抑制mRNA功能。在拴系记者分析中，我们确定了具有抑制活性的GIGYF2的三个独立域。在这个实验中 GIGYF2介导的抑制独立于4EHP，但很大程度上取决于GIGYF2通过多个接口募集的CCR4 / NOT复合物。重要的是，我们表明GIGYF2是一种RBP，并首次确定了概括4EHP依赖性抑制的内源性mRNA靶点。总而言之，我们建议GIGYF2具有两种不同的抑制机制：一种依赖于4EHP结合，主要影响翻译；另一种则依赖于4EHP结合。另一个是不依赖4EHP的，涉及CCR4 / NOT复合物及其去烯基化活性。我们建议GIGYF2具有两种不同的抑制机制：一种依赖于4EHP结合，主要影响翻译；另一种则依赖于4EHP结合。另一个是不依赖4EHP的，涉及CCR4 / NOT复合物及其去烯基化活性。我们建议GIGYF2具有两种不同的抑制机制：一种依赖于4EHP结合，主要影响翻译；另一种则依赖于4EHP结合。另一个是不依赖4EHP的，涉及CCR4 / NOT复合物及其去烯基化活性。