Polyamine Control of Translation Elongation Regulates Start Site Selection on Antizyme Inhibitor mRNA via Ribosome Queuing
Polyamine Control of Translation Elongation Regulates Start Site Selection on Antizyme Inhibitor mRNA via Ribosome Queuing
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DOI：
10.1016/j.molcel.2018.03.015
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发表时间：
2018-04-19
期刊：
影响因子：
16
通讯作者：
Dever, Thomas E.
中科院分区：
文献类型：
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作者：
Ivanov, Ivaylo P.;Shin, Byung-Sik;Dever, Thomas E.
翻译起始通常仅限于 AUG 密码子，扫描真核核糖体无法有效识别近同源密码子。我们表明，在暂停的延伸核糖体后面扫描核糖体的排队促进了上游弱起始位点的起始。核糖体分析揭示了抗酶抑制剂 1 (AZIN1) mRNA 的抑制性非 AUG 起始上游保守编码区 (uCC) 中保守的 Pro-Pro-Trp (PPW) 基序上核糖体延长的多胺依赖性暂停，编码细胞多胺合成的调节剂。 PPW 基序的突变会损害 uCC 上游近同源 AUU 起始位点的起始并抑制 AZIN1 合成，而替代延伸暂停序列的替换会恢复 uCC 翻译。削弱核糖体负载会减少 uCC 翻译，并相反地抑制 AZIN1 合成。最后，我们确定翻译因子 eIF5A 作为 uCC 翻译多胺控制的传感器和效应器。我们提出，延长核糖体的停滞会触发扫描核糖体的排队，并通过将核糖体定位在起始密码子附近来促进启动。
Translation initiation is typically restricted to AUG codons, and scanning eukaryotic ribosomes inefficiently recognize near-cognate codons. We show that queuing of scanning ribosomes behind a paused elongating ribosome promotes initiation at upstream weak start sites. Ribosomal profiling reveals polyamine-dependent pausing of elongating ribosomes on a conserved Pro-Pro-Trp (PPW) motif in an inhibitory non-AUG-initiated upstream conserved coding region (uCC) of the antizyme inhibitor 1 (AZIN1) mRNA, encoding a regulator of cellular polyamine synthesis. Mutation of the PPW motif impairs initiation at the uCC's upstream near-cognate AUU start site and derepresses AZIN1 synthesis, whereas substitution of alternate elongation pause sequences restores uCC translation. Impairing ribosome loading reduces uCC translation and paradoxically derepresses AZIN1 synthesis. Finally, we identify the translation factor eIF5A as a sensor and effector for polyamine control of uCC translation. We propose that stalling of elongating ribosomes triggers queuing of scanning ribosomes and promotes initiation by positioning a ribosome near the start codon.