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.

中文翻译：

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哺乳动物RNA衰变途径高度专业化，与翻译广泛相关。

RNA衰变对于mRNA转换和监测至关重要，在许多疾病中都被错误调节。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否发挥专门作用还是冗余作用。细胞质途径和翻译联系特别神秘。通过直接分析衰变因子靶标和小鼠胚胎干细胞（mESCs）中的正常翻译与异常翻译，我们发现了广泛的衰变途径专业化和与翻译的串扰。XRN1（5'-3'）介导细胞质的大量mRNA转换，而SKIV2L（3'-5'）被核糖体普遍招募，处理异常翻译并有时调节mRNA丰度。进一步探索翻译监控发现，AVEN和FOCAD是SKIV2L相互作用子。AVEN可以防止核糖体停滞在结构化区域，否则需要SKIV2L清除。该途径对于组蛋白翻译，上游开放阅读框（uORF）调节以及抵消小ORF上的核糖体阻滞至关重要。总之，我们发现了哺乳动物RNA衰变途径的关键靶标，组成和功能，以及与翻译的广泛偶联。