mTOR- and LARP1-dependent regulation of TOP mRNA poly(A) tail and ribosome loading
mTOR- and LARP1-dependent regulation of TOP mRNA poly(A) tail and ribosome loading
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DOI：
10.1016/j.celrep.2022.111548
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发表时间：
2022-10-25
期刊：
影响因子：
8.8
通讯作者：
Hoshino, Shin-ichi
中科院分区：
文献类型：
--
作者：
Ogami, Koichi;Oishi, Yuka;Hoshino, Shin-ichi
编码蛋白质合成机制的 5' 末端寡嘧啶 (TOP) mRNA 的翻译受到氨基酸感应 mTOR 通路的严格调控。然而，其调控机制仍然难以捉摸。在这里，我们证明在 mTOR 活性/富含氨基酸的条件下，TOP mRNA 翻译与其聚腺苷酸尾长度呈正相关，这表明 TOP mRNA 受到转录后聚腺苷酸尾长度调节的控制。与此相一致的是，TOP mRNA 的尾长会随着氨基酸的可用性而动态波动。在 mTOR 活性/氨基酸丰富的条件下，poly(A) 尾会缩短，而长尾 TOP mRNA 在 mTOR 无活性/氨基酸匮乏 (AAS) 条件下会积累。 RNA 结合蛋白 LARP1 在这个过程中是不可或缺的。 LARP1 与非经典聚腺苷酸聚合酶相互作用并诱导靶标的转录后聚腺苷酸化。我们的研究结果表明，LARP1 有助于 AAS 下具有长聚腺苷酸尾的 TOP mRNA 的选择性积累，从而加速核糖体加载到 TOP mRNA 上，以在 AAS 后恢复翻译。
Translation of 5' terminal oligopyrimidine (TOP) mRNAs encoding the protein synthesis machinery is strictly regulated by an amino-acid-sensing mTOR pathway. However, its regulatory mechanism remains elusive. Here, we demonstrate that TOP mRNA translation positively correlates with its poly(A) tail length under mTOR active/amino-acid-rich conditions, suggesting that TOP mRNAs are post-transcriptionally controlled by poly(A) tail-length regulation. Consistent with this, the tail length of TOP mRNAs dynamically fluctuates in response to amino acid availability. The poly(A) tail shortens under mTOR active/amino-acid-rich conditions, whereas the long-tailed TOP mRNAs accumulate under mTOR inactive/amino-acid-starved (AAS) conditions. An RNA-binding protein, LARP1, is indispensable for the process. LARP1 interacts with non-canonical poly(A) polymerases and induces post-transcriptional polyadenylation of the target. Our findings illustrate that LARP1 contributes to the selective accumulation of TOP mRNAs with long poly(A) tails under AAS, re-sulting in accelerated ribosomal loading onto TOP mRNAs for the resumption of translation after AAS.