Department of Biological Chemistry, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya 467-8603, Japan.
Department of Biological Chemistry, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya 467-8603, Japan.
Cell Rep. 2022 Oct 25;41(4):111548. doi: 10.1016/j.celrep.2022.111548.
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, resulting in accelerated ribosomal loading onto TOP mRNAs for the resumption of translation after AAS.
5' 端寡嘧啶（TOP）mRNA 编码蛋白质合成机制的翻译受到严格调控，受氨基酸感应 mTOR 通路调控。然而，其调控机制仍不清楚。在这里，我们证明在 mTOR 活跃/氨基酸丰富条件下，TOP mRNA 的翻译与 poly(A) 尾巴长度呈正相关，表明 TOP mRNAs 受 poly(A) 尾巴长度调控的转录后调控。与此一致，TOP mRNAs 的尾巴长度会根据氨基酸的可用性而动态波动。在 mTOR 活跃/氨基酸丰富的条件下，poly(A) 尾巴缩短，而在 mTOR 不活跃/氨基酸饥饿（AAS）的条件下，长尾 TOP mRNAs 积累。一种 RNA 结合蛋白 LARP1 对这一过程不可或缺。LARP1 与非典型 poly(A) 聚合酶相互作用，并诱导靶标转录后的多聚腺苷酸化。我们的研究结果表明，LARP1 有助于在 AAS 条件下选择性积累具有长 poly(A) 尾巴的 TOP mRNAs，从而加速核糖体加载到 TOP mRNAs 上，以在 AAS 后恢复翻译。
