mTORC1 promotes TOP mRNA translation through site-specific phosphorylation of LARP1.
mTORC1 promotes TOP mRNA translation through site-specific phosphorylation of LARP1.
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DOI：
10.1093/nar/gkaa1239
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发表时间：
2021-04-06
影响因子：
14.9
通讯作者：
Fonseca BD
中科院分区：
文献类型：
--
作者：
Jia JJ;Lahr RM;Solgaard MT;Moraes BJ;Pointet R;Yang AD;Celucci G;Graber TE;Hoang HD;Niklaus MR;Pena IA;Hollensen AK;Smith EM;Chaker-Margot M;Anton L;Dajadian C;Livingstone M;Hearnden J;Wang XD;Yu Y;Maier T;Damgaard CK;Berman AJ;Alain T;Fonseca BD
LARP 1是TOP mRNA翻译的关键阻遏物。它结合m7 Gppp帽部分和TOP mRNA的相邻5′TOP基序，从而阻碍eIF 4F复合物在这些转录物上的组装。mTORC 1通过LARP 1控制TOP mRNA的翻译，但其机制的细节尚不清楚。在这里，我们阐明mTORC 1控制LARP 1的翻译抑制活性的机制。我们证明，mTORC 1磷酸化LARP 1在体外和体内，活性，有效地抑制雷帕霉素和torin 1。我们发现26雷帕霉素敏感的磷酸丝氨酸和苏氨酸残基LARP 1分布在7个集群。我们的数据表明，位于近端的m7 Gppp帽结合DM 15区域的残基簇的磷酸化对雷帕霉素特别敏感，并调节LARP 1的RNA结合和翻译抑制活性。我们的研究结果揭示了一种新的翻译控制模型，其中LARP 1的La模块（LaMod）和DM 15区域（两者都可以直接与TOP mRNA相互作用）受到差异调节：LaMod仍然与PABP组成型结合（不考虑mTORC 1的激活状态），而C-末端DM 15“摆动钩”接合TOP mRNA 5′-末端以抑制翻译，但仅在mTORC 1抑制的条件下。
LARP1 is a key repressor of TOP mRNA translation. It binds the m7Gppp cap moiety and the adjacent 5′TOP motif of TOP mRNAs, thus impeding the assembly of the eIF4F complex on these transcripts. mTORC1 controls TOP mRNA translation via LARP1, but the details of the mechanism are unclear. Herein we elucidate the mechanism by which mTORC1 controls LARP1’s translation repression activity. We demonstrate that mTORC1 phosphorylates LARP1 in vitro and in vivo, activities that are efficiently inhibited by rapamycin and torin1. We uncover 26 rapamycin-sensitive phospho-serine and -threonine residues on LARP1 that are distributed in 7 clusters. Our data show that phosphorylation of a cluster of residues located proximally to the m7Gppp cap-binding DM15 region is particularly sensitive to rapamycin and regulates both the RNA-binding and the translation inhibitory activities of LARP1. Our results unravel a new model of translation control in which the La module (LaMod) and DM15 region of LARP1, both of which can directly interact with TOP mRNA, are differentially regulated: the LaMod remains constitutively bound to PABP (irrespective of the activation status of mTORC1), while the C-terminal DM15 ‘pendular hook’ engages the TOP mRNA 5′-end to repress translation, but only in conditions of mTORC1 inhibition.
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影响因子：
4.8
作者：
Fonseca, Bruno D.;Smith, Ewan M.;Proud, Christopher G.
通讯作者：
Proud, Christopher G.
影响因子：
3.5
作者：
Biberman, Y;Meyuhas, O
通讯作者：
Meyuhas, O
影响因子：
10.5
作者：
Damgaard, Christian Kroun;Lykke-Andersen, Jens
通讯作者：
Lykke-Andersen, Jens
影响因子：
4.1
作者：
Fonseca, Bruno D.;Lee, Vivian H. -Y.;Proud, Christopher G.
通讯作者：
Proud, Christopher G.
影响因子：
4.8
作者：
Ferguson, G;Mothe-Satney, I;Lawrence, JC
通讯作者：
Lawrence, JC