Specific tRNAs promote mRNA decay by recruiting the CCR4-NOT complex to translating ribosomes

• 成果类型: Article
• 署名作者: Zhu, Xiaoqiang; Cruz, Victor Emmanuel; Zhang, He; Erzberger, Jan P.; Mendell, Joshua T.
• 署名单位: University of Texas System; University of Texas Southwestern Medical Center; University of Texas System; University of Texas Southwestern Medical Center; University of Texas System; University of Texas Southwestern Medical Center; University of Texas System; University of Texas Southwestern Medical Center; University of Texas System; University of Texas Southwestern Medical Center; University of Texas System; University of Texas Southwestern Medical Center; University of Texas System; University of Texas Southwestern Medical Center; Howard Hughes Medical Institute; University of Texas System; University of Texas Southwestern Medical Center
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-13413
• DOI: 10.1126/science.adq8587
• 发表日期: 2024-11-22
• 关键词: codon optimality; protein; expression; deadenylation; RECOGNITION; mechanism; EFFICIENCY; element; target; usage

摘要

The CCR4-NOT complex is a major regulator of eukaryotic messenger RNA (mRNA) stability. Slow decoding during translation promotes association of CCR4-NOT with ribosomes, accelerating mRNA degradation. We applied selective ribosome profiling to further investigate the determinants of CCR4-NOT recruitment to ribosomes in mammalian cells. This revealed that specific arginine codons in the P-site are strong signals for ribosomal recruitment of human CNOT3, a CCR4-NOT subunit. Cryo-electron microscopy and transfer RNA (tRNA) mutagenesis demonstrated that the D-arms of select arginine tRNAs interact with CNOT3 and promote its recruitment whereas other tRNA D-arms sterically clash with CNOT3. These effects link codon content to mRNA stability. Thus, in addition to their canonical decoding function, tRNAs directly engage regulatory complexes during translation, a mechanism we term P-site tRNA-mediated mRNA decay.