mTOR inhibition reprograms cellular proteostasis by regulating eIF3D-mediated selective mRNA translation and promotes cell phenotype switching.
mTOR inhibition reprograms cellular proteostasis by regulating eIF3D-mediated selective mRNA translation and promotes cell phenotype switching.
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MTOR抑制通过调节eIF3D介导的选择性mRNA翻译来重新编程细胞蛋白平衡，并促进细胞表型转换。
DOI：
10.1016/j.celrep.2023.112868
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发表时间：
2023-08-29
期刊：
影响因子：
8.8
通讯作者：
中科院分区：
文献类型：
--
作者：
细胞根据环境和自身需要维持并动态改变其蛋白质组。雷帕霉素（Mechanistic target of rapamycin, mTOR）是蛋白质组稳态的关键调控因子。因此，mTOR的失调会导致蛋白质平衡的改变和随之而来的疾病的进展，包括癌症。基于mTOR信号的生理和临床重要性，我们研究了mTOR反馈信号、蛋白酶抑制和细胞命运。在这里，我们发现mTOR靶向抑制eif4e介导的帽依赖翻译，但反馈信号激活翻译起始因子，真核翻译起始因子3D (eIF3D)，以维持替代的非规范翻译机制。重要的是，eif3d介导的蛋白质合成使细胞表型从增殖性转变为更具迁移性。eIF3D与mRNA结合蛋白如异质核核糖核蛋白F （hnRNPF）、异质核核糖核蛋白K （hnRNPK）和干燥综合征抗原B （SSB）合作，支持mTOR抑制后的选择性mRNA翻译。上调和激活胰岛素受体(INSR)/胰岛素样生长因子1受体(IGF1R)/胰岛素受体底物（IRS）和白细胞介素6信号转导器(IL-6ST)/Janus激酶(JAK)/信号转导和转录激活器（STAT）信号转导的蛋白。我们的研究强调了细胞建立蛋白质稳态动态变化和由此产生的表型转换的机制。mTOR是细胞蛋白质组的主要调节因子，从而控制细胞的生长和增殖。Shin等人发现，细胞通过与rna结合蛋白合作促进eif3d依赖性的选择性mRNA翻译，同时抑制eif4e介导的翻译，从而动态改变其蛋白质组以响应mTOR的抑制。
Cells maintain and dynamically change their proteomes according to the environment and their needs. Mechanistic target of rapamycin (mTOR) is a key regulator of proteostasis, homeostasis of the proteome. Thus, dysregulation of mTOR leads to changes in proteostasis and the consequent progression of diseases, including cancer. Based on the physiological and clinical importance of mTOR signaling, we investigated mTOR feedback signaling, proteostasis, and cell fate. Here, we reveal that mTOR targeting inhibits eIF4E-mediated cap-dependent translation, but feedback signaling activates a translation initiation factor, eukaryotic translation initiation factor 3D (eIF3D), to sustain alternative non-canonical translation mechanisms. Importantly, eIF3D-mediated protein synthesis enables cell phenotype switching from proliferative to more migratory. eIF3D cooperates with mRNA-binding proteins such as heterogeneous nuclear ribonucleoprotein F (hnRNPF), heterogeneous nuclear ribonucleoprotein K (hnRNPK), and Sjogren syndrome antigen B (SSB) to support selective mRNA translation following mTOR inhibition, which upregulates and activates proteins involved in insulin receptor (INSR)/insulin-like growth factor 1 receptor (IGF1R)/insulin receptor substrate (IRS) and interleukin 6 signal transducer (IL-6ST)/Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling. Our study highlights the mechanisms by which cells establish the dynamic change of proteostasis and the resulting phenotype switch. mTOR is the primary regulator of the cellular proteome, thereby governing cell growth and proliferation. Shin et al. reveal that cells dynamically change their proteome in response to mTOR inhibition by promoting eIF3D-dependent selective mRNA translation in cooperation with RNA-binding proteins while inhibiting eIF4E-mediated translation.
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影响因子：
64.5
作者：
Huttlin EL;Jedrychowski MP;Elias JE;Goswami T;Rad R;Beausoleil SA;Villén J;Haas W;Sowa ME;Gygi SP
通讯作者：
Gygi SP
DOI：
10.1098/rstb.2016.0176
发表时间：
2017-03-19
期刊：
Philosophical transactions of the Royal Society of London. Series B, Biological sciences
影响因子：
--
作者：
Cate JH
通讯作者：
Cate JH
影响因子：
16
作者：
Guan BJ;van Hoef V;Jobava R;Elroy-Stein O;Valasek LS;Cargnello M;Gao XH;Krokowski D;Merrick WC;Kimball SR;Komar AA;Koromilas AE;Wynshaw-Boris A;Topisirovic I;Larsson O;Hatzoglou M
通讯作者：
Hatzoglou M
影响因子：
81.5
作者：
Henske, Elizabeth P.;Jozwiak, Sergiusz;Thiele, Elizabeth A.
通讯作者：
Thiele, Elizabeth A.
影响因子：
56.9
作者：
Dorrello, N. Valerio;Peschiaroli, Angelo;Pagano, Michele
通讯作者：
Pagano, Michele