TAp73 contributes to the oxidative stress response by regulating protein synthesis.
TAp73 contributes to the oxidative stress response by regulating protein synthesis.
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DOI：
10.1073/pnas.1718531115
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发表时间：
2018-06-12
影响因子：
11.1
通讯作者：
Melino G
中科院分区：
文献类型：
--
作者：
Marini A;Rotblat B;Sbarrato T;Niklison-Chirou MV;Knight JRP;Dudek K;Jones C;Bushell M;Knight RA;Amelio I;Willis AE;Melino G
氧化应激是衰老相关疾病的关键因素，包括神经变性、癌症和心血管疾病。在这里，我们证明了p53家族转录因子TAp73通过参与蛋白质合成的控制来促进氧化应激反应。mRNA翻译的调节确保了克服压力的迅速和有效的方法，并且TAp73缺失导致异常的核糖体生物合成和受损的蛋白质合成。特别地，TAp73对于维持线粒体转录物响应于氧化应激的主动翻译是重要的，从而促进线粒体活性，这有助于适应应激条件。因此，我们的数据揭示了TAp73在调节蛋白质合成中的意想不到的作用，该蛋白质合成负责其稳态能力。TAp73是一种转录因子，在大脑发育、衰老和癌症中起关键作用。在细胞水平，TAp73是一个关键的稳态维持因子，特别是在氧化应激后。虽然主要的研究集中在TAp73的转录活性表明TAp73的细胞代谢的贡献，其在氧化还原稳态的作用机制尚未完全阐明。在这里，我们表明，TAp73有助于通过参与蛋白质合成的控制氧化应激反应。mRNA翻译的调节在应激反应期间的细胞内稳态中占据中心位置，通常通过降低蛋白质合成的总体速率和促进特定mRNA的翻译。TAp73缺失导致异常的核糖体RNA（rRNA）加工和受损的蛋白质合成。特别是，多核糖体谱显示，TAp73促进编码rRNA加工因子的mRNA在多核糖体中的整合，支持它们的翻译。同时，TAp73缺失导致对氧化应激的敏感性增加，这与ATP水平降低、AMPK过度活化和翻译缺陷相关。TAp73对于维持线粒体转录物的主动翻译以响应氧化应激是重要的，从而促进线粒体活性。我们的研究结果表明，TAp73通过影响翻译机制，促进特定线粒体转录本的翻译，从而有助于氧化还原稳态。这项研究确定了TAp73促进氧化应激反应的机制，并描述了TAp73在调节蛋白质合成中完全出乎意料的作用。
Oxidative stress is a critical contributor to aging-associated diseases, including neurodegeneration, cancer, and cardiovascular disease. Here, we demonstrate that the p53 family transcription factor TAp73 contributes to the oxidative stress response by participating in the control of protein synthesis. Regulation of mRNA translation ensures a prompt and efficient method to overcome stress, and TAp73 depletion results in aberrant ribosomal biogenesis and impaired protein synthesis. In particular, TAp73 is important for maintaining active translation of mitochondrial transcripts in response to oxidative stress, thus promoting mitochondrial activity that contributes to adaptation to stress conditions. Our data therefore reveal an unexpected role for TAp73 in regulating protein synthesis responsible for its homeostatic ability. TAp73 is a transcription factor that plays key roles in brain development, aging, and cancer. At the cellular level, TAp73 is a critical homeostasis-maintaining factor, particularly following oxidative stress. Although major studies focused on TAp73 transcriptional activities have indicated a contribution of TAp73 to cellular metabolism, the mechanisms underlying its role in redox homeostasis have not been completely elucidated. Here we show that TAp73 contributes to the oxidative stress response by participating in the control of protein synthesis. Regulation of mRNA translation occupies a central position in cellular homeostasis during the stress response, often by reducing global rates of protein synthesis and promoting translation of specific mRNAs. TAp73 depletion results in aberrant ribosomal RNA (rRNA) processing and impaired protein synthesis. In particular, polysomal profiles show that TAp73 promotes the integration of mRNAs that encode rRNA-processing factors in polysomes, supporting their translation. Concurrently, TAp73 depletion causes increased sensitivity to oxidative stress that correlates with reduced ATP levels, hyperactivation of AMPK, and translational defects. TAp73 is important for maintaining active translation of mitochondrial transcripts in response to oxidative stress, thus promoting mitochondrial activity. Our results indicate that TAp73 contributes to redox homeostasis by affecting the translational machinery, facilitating the translation of specific mitochondrial transcripts. This study identifies a mechanism by which TAp73 contributes to the oxidative stress response and describes a completely unexpected role for TAp73 in regulating protein synthesis.
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影响因子：
64.5
作者：
Leprivier G;Remke M;Rotblat B;Dubuc A;Mateo AR;Kool M;Agnihotri S;El-Naggar A;Yu B;Somasekharan SP;Faubert B;Bridon G;Tognon CE;Mathers J;Thomas R;Li A;Barokas A;Kwok B;Bowden M;Smith S;Wu X;Korshunov A;Hielscher T;Northcott PA;Galpin JD;Ahern CA;Wang Y;McCabe MG;Collins VP;Jones RG;Pollak M;Delattre O;Gleave ME;Jan E;Pfister SM;Proud CG;Derry WB;Taylor MD;Sorensen PH
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影响因子：
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作者：
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通讯作者：
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影响因子：
10.5
作者：
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影响因子：
11.4
作者：
Soudet, Julien;Gelugne, Jean-Paul;Mougin, Annie
通讯作者：
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