Repression of mRNA translation initiation by GIGYF1 via blocking the eIF3-eIF4G1 interaction
Repression of mRNA translation initiation by GIGYF1 via blocking the eIF3-eIF4G1 interaction
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DOI：
10.1101/2023.10.14.562322
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发表时间：
2023-10
期刊：
影响因子：
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通讯作者：
Jung-Hyun Choi;Jun Luo;Geoffrey G. Hesketh;Shuyue Guo;Angelos Pistofidis;Reese Jalal Ladak;Yuxin An;Tommy Alain;T. Schmeing;A. Gingras;T. Duchaine;Xu Zhang;Nahum Sonenberg;S. M. Jafarnejad
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文献类型：
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作者：
Jung-Hyun Choi;Jun Luo;Geoffrey G. Hesketh;Shuyue Guo;Angelos Pistofidis;Reese Jalal Ladak;Yuxin An;Tommy Alain;T. Schmeing;A. Gingras;T. Duchaine;Xu Zhang;Nahum Sonenberg;S. M. Jafarnejad
病毒通常会干扰真核翻译起始因子 4G1 (eIF4G1) 的功能，该因子是 eIF3 复合物和核糖体募集至 mRNA 的关键因素。这导致一般宿主蛋白质合成受到抑制，并将核糖体重定向至病毒 mRNA。某些病毒还选择性地抑制参与宿主抗病毒反应的 mRNA 的翻译。 GIGYF2 及其相互作用的帽结合蛋白 4EHP 能够对 microRNA 和 RNA 结合蛋白 (RBP) 介导的 mRNA 翻译进行转录特异性抑制。 RNA 病毒（例如 SARS-CoV-2）利用 GIGYF2/4EHP 复合物选择性抑制转录本的翻译，例如编码抗病毒细胞因子干扰素 β (IFN-β) 的 Ifnb1 mRNA。在此，我们揭示了 GIGYF1（GIGYF2 的旁系同源物）通过独立于 4EHP 的独特机制强力抑制细胞 mRNA 翻译。当 RBP 招募至靶 mRNA 时，GIGYF1 的 C 末端区域在 eIF3-eIF4G1 相互作用界面处与 eIF3 亚基结合。这会破坏 eIF3 与 eIF4G1 的结合，导致 mRNA 特异性翻译抑制。这种机制对宿主细胞对病毒感染的反应产生深远的影响。 GIGYF1 的缺失会通过去抑制 Ifnb1 mRNA 翻译来诱导强大的免疫反应。总体而言，我们的研究强调了 GIGYF1 独特的翻译调控机制，其中涉及隔离 eIF3 并废除其与 eIF4G1 的结合。与 GIGYF1 相互作用的 RBP 可利用这种机制来特异性抑制其靶标 mRNA 的翻译，从而显着影响关键的生物过程，包括宿主与病原体的相互作用。
Viruses commonly interfere with the function of the eukaryotic translation initiation factor 4G1 (eIF4G1), a pivotal factor in the recruitment of the eIF3 complex and ribosome to the mRNA. This results in the inhibition of general host protein synthesis and redirecting ribosomes toward viral mRNAs. Certain viruses also selectively repress the translation of mRNAs involved in the host antiviral response. GIGYF2 and its interacting cap-binding protein 4EHP enable the transcript-specific repression of mRNA translation mediated by microRNAs and RNA-binding proteins (RBPs). RNA viruses, such as SARS-CoV-2, exploit the GIGYF2/4EHP complex to selectively repress the translation of transcripts such as Ifnb1 mRNA, which encodes the antiviral cytokine Interferon β (IFN-β). Herein, we reveal that GIGYF1, a paralogue of GIGYF2, robustly represses cellular mRNA translation through a distinct mechanism independent of 4EHP. Upon recruitment to a target mRNA by RBPs, the C-terminal region of GIGYF1 binds to subunits of eIF3 at the interaction interface of eIF3-eIF4G1. This disrupts binding of eIF3 to eIF4G1, resulting in mRNA-specific translational repression. This mechanism exerts profound influences on the host cell’s response to viral infection. Depletion of GIGYF1 induces a robust immune response by derepressing Ifnb1 mRNA translation. Overall, our study highlights a unique mechanism of translational regulation by GIGYF1 that involves sequestering eIF3 and abrogating its binding to eIF4G1. This mechanism can be utilized by RBPs that interact with GIGYF1 to specifically repress the translation of their target mRNAs, significantly affecting critical biological processes, including host-pathogen interactions.