Coupled activation and degradation of eEF2K regulates protein synthesis in response to genotoxic stress.
Coupled activation and degradation of eEF2K regulates protein synthesis in response to genotoxic stress.
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DOI：
10.1126/scisignal.2002718
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发表时间：
2012-06-05
影响因子：
7.3
通讯作者：
Guardavaccaro D
中科院分区：
文献类型：
--
作者：
Kruiswijk F;Yuniati L;Magliozzi R;Low TY;Lim R;Bolder R;Mohammed S;Proud CG;Heck AJ;Pagano M;Guardavaccaro D
EEF2K是一种通过磷酸化真核细胞延长因子2(EEF2)来控制肽链延长速度的激酶，eEF2是一种通过促进核糖体从A位到P位的易位来介导核糖体沿mRNA移动的蛋白质。EEF2K介导的eEF2在Thr56上的磷酸化降低了它与核糖体的亲和力，从而抑制了延伸。在这里，我们表明，作为对遗传毒性应激的反应，eEF2K通过AMPK介导的Ser398上的磷酸化而被激活。激活的eEF2K使eEF2磷酸化，并在伸长阶段诱导核糖体暂时减慢。随后，在检查点沉默期间，eEF2K被泛素-蛋白酶体系统通过SCFβTrCP泛素连接酶降解，以允许快速恢复翻译延伸。这一事件需要在典型的βTrCP结合域上进行eEF2K自动磷酸化。在检查点沉默过程中不能降解eEF2K导致了Thr56上eEF2的持续磷酸化和翻译延长的延迟恢复。我们的研究在DNA损伤信号和翻译延长之间建立了一个重要的联系。
eEF2K is a kinase that controls the rate of peptide chain elongation by phosphorylating eukaryotic Elongation Factor 2 (eEF2), the protein that mediates the movement of the ribosome along the mRNA by promoting translocation from the A to the P site. eEF2K-mediated phosphorylation of eEF2 on Thr56 decreases its affinity for the ribosome, thereby inhibiting elongation. Here we show that in response to genotoxic stress, eEF2K is activated by AMPK-mediated phosphorylation on Ser398. Activated eEF2K phosphorylates eEF2 and induces a temporary ribosomal slowdown at the stage of elongation. Subsequently, during checkpoint silencing, eEF2K is degraded by the ubiquitin-proteasome system via the SCFβTrCP ubiquitin ligase to allow rapid resumption of translation elongation. This event requires eEF2K autophosphorylation on a canonical βTrCP-binding domain. The inability to degrade eEF2K during checkpoint silencing caused sustained phosphorylation of eEF2 on Thr56 and delayed resumption of translation elongation. Our study establishes an important link between DNA damage signaling and translation elongation.
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影响因子：
64.5
作者：
Bassermann, Florian;Frescas, David;Guardavaccaro, Daniele;Busino, Luca;Peschiaroli, Angelo;Pagano, Michele
通讯作者：
Pagano, Michele
影响因子：
10.5
作者：
Jin, JP;Shirogane, T;Harper, JW
通讯作者：
Harper, JW
影响因子：
56.9
作者：
Dorrello, N. Valerio;Peschiaroli, Angelo;Pagano, Michele
通讯作者：
Pagano, Michele
影响因子：
7.5
作者：
Efeyan A;Sabatini DM
通讯作者：
Sabatini DM
影响因子：
4.8
作者：
Browne, GJ;Finn, SG;Proud, CG
通讯作者：
Proud, CG