N6-Methyladenosine (m6A) is the most prevalent mRNA modification. Its biological function primarily relies on its "Reader" protein, such as YTHDC2. Previous studies have shown that YTHDC2 downregulation is a pro-carcinogenic phenomenon in lung adenocarcinoma (LUAD). However, further investigation is needed to understand the molecular mechanisms of downstream genes and the associated biological phenomena following YTHDC2 downregulation. Here, we found that YTHDC2 knockout upregulated exosome content in LUAD. Following YTHDC2 knockout, the mRNA levels of OAS family members (OASs) and IFIT family members (IFITs) also decreased; and inhibition of OASs and IFITs could promote exosome content. Several m6A modification sites on the NT domain of OASs and the TPR12 domain of IFITs were found to increase the stability of OASs and IFITs in a YTHDC2-dependent manner. OASs and IFITs affected exosome content through target genes including RAB5A, RAB7 and RAB11A, and three arginine (R) amino acids on IFITs were critical for combination IFITs with targeted RAB mRNAs and subsequent degradation. Simultaneously, OASs degraded targeted RABs through RNAseL. Additionally, mutual bindings between OASs and IFITs were critical for their target gene degradation. Collectively, the above findings might provide a theoretical basis for the treatment of LUAD patients with low YTHDC2 expression.

中文翻译：

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m6A 阅读器 YTHDC2 的下调通过抑制 IFIT 和 OAS 家族成员上调肺腺癌中的外泌体含量。


N6-甲基腺苷 (m6A) 是最常见的 mRNA 修饰。其生物学功能主要依赖于其“Reader”蛋白，如YTHDC2。先前的研究表明，YTHDC2 下调是肺腺癌（LUAD）中的一种促癌现象。然而，需要进一步研究以了解下游基因的分子机制以及 YTHDC2 下调后的相关生物学现象。在这里，我们发现 YTHDC2 敲除上调了 LUAD 中的外泌体含量。 YTHDC2敲除后，OAS家族成员（OAS）和IFIT家族成员（IFIT）的mRNA水平也下降；抑制 OAS 和 IFIT 可以促进外泌体含量。发现 OAS 的 NT 结构域和 IFIT 的 TPR12 结构域上的几个 m6A 修饰位点以 YTHDC2 依赖性方式增加了 OAS 和 IFIT 的稳定性。 OAS 和 IFIT 通过 RAB5A、RAB7 和 RAB11A 等靶基因影响外泌体含量，并且 IFIT 上的三个精氨酸 (R) 氨基酸对于 IFIT 与靶向 RAB mRNA 的组合以及随后的降解至关重要。同时，OAS 通过 RNAseL 降解目标 RAB。此外，OAS 和 IFIT 之间的相互结合对于它们的靶基因降解至关重要。总的来说，上述研究结果可能为YTHDC2低表达的LUAD患者的治疗提供理论依据。