Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, 4058 Basel, Switzerland.
Center for Integrative Genomics, University of Lausanne, 1015 Lausanne, Switzerland.
Mol Cell. 2020 Mar 19;77(6):1222-1236.e13. doi: 10.1016/j.molcel.2020.01.007. Epub 2020 Feb 10.
RNA decay is crucial for mRNA turnover and surveillance and misregulated in many diseases. This complex system is challenging to study, particularly in mammals, where it remains unclear whether decay pathways perform specialized versus redundant roles. Cytoplasmic pathways and links to translation are particularly enigmatic. By directly profiling decay factor targets and normal versus aberrant translation in mouse embryonic stem cells (mESCs), we uncovered extensive decay pathway specialization and crosstalk with translation. XRN1 (5'-3') mediates cytoplasmic bulk mRNA turnover whereas SKIV2L (3'-5') is universally recruited by ribosomes, tackling aberrant translation and sometimes modulating mRNA abundance. Further exploring translation surveillance revealed AVEN and FOCAD as SKIV2L interactors. AVEN prevents ribosome stalls at structured regions, which otherwise require SKIV2L for clearance. This pathway is crucial for histone translation, upstream open reading frame (uORF) regulation, and counteracting ribosome arrest on small ORFs. In summary, we uncovered key targets, components, and functions of mammalian RNA decay pathways and extensive coupling to translation.
RNA 衰变对于 mRNA 的周转和监控至关重要，在许多疾病中都存在失调。这个复杂的系统很难研究，特别是在哺乳动物中，目前尚不清楚衰变途径是执行专门的还是冗余的作用。细胞质途径和与翻译的联系尤其神秘。通过直接分析小鼠胚胎干细胞（mESCs）中衰变因子靶标和正常与异常翻译的情况，我们发现了广泛的衰变途径专门化以及与翻译的交叉作用。XRN1（5'-3'）介导细胞质大量 mRNA 的周转，而 SKIV2L（3'-5'）则被核糖体普遍招募，解决异常翻译问题，有时还调节 mRNA 的丰度。进一步探索翻译监控揭示了 AVEN 和 FOCAD 是 SKIV2L 的相互作用蛋白。AVEN 可防止核糖体在结构区域停滞，否则这些区域需要 SKIV2L 进行清除。该途径对于组蛋白翻译、上游开放阅读框 (uORF) 的调控以及对抗核糖体在小 ORF 上的停滞至关重要。总之，我们揭示了哺乳动物 RNA 衰变途径的关键靶标、组成部分和功能，以及与翻译的广泛偶联。
