Tumor cells often exploit the protein translation machinery, resulting in enhanced protein expression essential for tumor growth. Since canonical translation initiation is often suppressed because of cell stress in the tumor microenvironment, non-canonical translation initiation mechanisms become particularly important for shaping the tumor proteome. EIF4G2 is a non-canonical translation initiation factor that mediates internal ribosome entry site (IRES)- and uORF-dependent initiation mechanisms, which can be used to modulate protein expression in cancer. Here, we explored the contribution of EIF4G2 to cancer by screening the COSMIC database for EIF4G2 somatic mutations in cancer patients. Functional examination of missense mutations revealed deleterious effects on EIF4G2 protein-protein interactions and, importantly, on its ability to mediate non-canonical translation initiation. Specifically, one mutation, R178Q, led to reductions in protein expression and near-complete loss of function. Two other mutations within the MIF4G domain specifically affected EIF4G2's ability to mediate IRES-dependent translation initiation but not that of target mRNAs with uORFs. These results shed light on both the structure-function of EIF4G2 and its potential tumor suppressor effects.

中文翻译：

---

EIF4G2 非规范翻译起始因子中与癌症相关的功能丧失突变。

肿瘤细胞经常利用蛋白质翻译机制，导致肿瘤生长必需的蛋白质表达增强。由于肿瘤微环境中的细胞应激通常会抑制规范翻译起始，因此非规范翻译起始机制对于塑造肿瘤蛋白质组变得尤为重要。EIF4G2 是一种非规范翻译起始因子，可介导内部核糖体进入位点 (IRES) 和 uORF 依赖性起始机制，可用于调节癌症中的蛋白质表达。在这里，我们通过筛选 COSMIC 数据库中癌症患者的 EIF4G2 体细胞突变，探讨了 EIF4G2 对癌症的贡献。错义突变的功能检查揭示了对 EIF4G2 蛋白质-蛋白质相互作用的有害影响，更重要的是，对其介导非规范翻译起始的能力产生有害影响。具体来说，一种突变 R178Q 导致蛋白质表达减少和功能几乎完全丧失。MIF4G 结构域内的另外两个突变特异性影响 EIF4G2 介导 IRES 依赖性翻译起始的能力，但不影响具有 uORF 的靶 mRNA 的能力。这些结果揭示了 EIF4G2 的结构功能及其潜在的肿瘤抑制作用。