Choi Jung-Hyun, Luo Jun, Hesketh Geoffrey G, Guo Shuyue, Pistofidis Angelos, Ladak Reese Jalal, An Yuxin, Naeli Parisa, Alain Tommy, Schmeing T Martin, Gingras Anne-Claude, Duchaine Thomas, Zhang Xu, Sonenberg Nahum, Jafarnejad Seyed Mehdi
Rosalind and Morris Goodman Cancer Institute, McGill University, Montreal, QC H3A 1A3, Canada.
Department of Biochemistry, McGill University, Montreal, QC H3A 1A3, Canada.
Sci Adv. 2024 Jul 19;10(29):eadl5638. doi: 10.1126/sciadv.adl5638. Epub 2024 Jul 17.
Viruses can selectively repress the translation of mRNAs involved in the antiviral response. RNA viruses exploit the Grb10-interacting GYF (glycine-tyrosine-phenylalanine) proteins 2 (GIGYF2) and eukaryotic translation initiation factor 4E (eIF4E) homologous protein 4EHP to selectively repress the translation of transcripts such as , which encodes the antiviral cytokine interferon-β (IFN-β). Herein, we reveal that GIGYF1, a paralog of GIGYF2, robustly represses cellular mRNA translation through a distinct 4EHP-independent mechanism. Upon recruitment to a target mRNA, GIGYF1 binds to subunits of eukaryotic translation initiation factor 3 (eIF3) at the eIF3-eIF4G1 interaction interface. This interaction disrupts the eIF3 binding to eIF4G1, resulting in transcript-specific translational repression. Depletion of GIGYF1 induces a robust immune response by derepressing IFN-β production. Our study highlights a unique mechanism of translational regulation by GIGYF1 that involves sequestering eIF3 and abrogating its binding to eIF4G1. This mechanism has profound implications for the host response to viral infections.
病毒能够选择性地抑制参与抗病毒反应的mRNA的翻译。RNA病毒利用与Grb10相互作用的GYF（甘氨酸 - 酪氨酸 - 苯丙氨酸）蛋白2（GIGYF2）和真核翻译起始因子4E（eIF4E）同源蛋白4EHP来选择性地抑制诸如编码抗病毒细胞因子干扰素-β（IFN-β）的转录本的翻译。在此，我们揭示了GIGYF2的旁系同源物GIGYF1通过一种独特的不依赖4EHP的机制强烈抑制细胞mRNA翻译。在被招募到靶mRNA后，GIGYF1在eIF3 - eIF4G1相互作用界面与真核翻译起始因子3（eIF3）的亚基结合。这种相互作用破坏了eIF3与eIF4G1的结合，导致转录本特异性的翻译抑制。GIGYF1的缺失通过解除对IFN-β产生的抑制而诱导强烈的免疫反应。我们的研究突出了GIGYF1独特的翻译调控机制，该机制涉及隔离eIF3并消除其与eIF4G1的结合。这种机制对宿主对病毒感染的反应具有深远影响。
