Upregulation of eIF5B controls cell-cycle arrest and specific developmental stages
Upregulation of eIF5B controls cell-cycle arrest and specific developmental stages
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DOI：
10.1073/pnas.1320477111
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发表时间：
2014-10-14
影响因子：
11.1
通讯作者：
Vasudevan, Shobha
中科院分区：
文献类型：
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作者：
Lee, Sooncheol;Truesdell, Samuel S.;Vasudevan, Shobha
增殖阻滞和不同的发育阶段改变和减少一般翻译，但保持正在进行的翻译。在这些条件下支持翻译的因素仍有待研究。我们研究了三种被认为降低了一般翻译的细胞状态中翻译因子的改变：未成熟非洲爪蟾卵母细胞、小鼠胚胎干细胞和生长因子剥夺后增殖哺乳动物细胞向静止（G0）的过渡状态。我们的数据显示，在这些条件下，真核翻译起始因子5B (eIF5B)（细菌起始因子IF2的真核同源物）的瞬间增加。eIF5B促进60S核糖体亚基连接和40S前亚基校对。eIF5B也被证明可以促进病毒和应激相关mrna的翻译，并间接有助于支持或稳定启动物甲硫基tRNA （tRNA- Met(i)）与核糖体的结合。我们发现在这三种情况下，eIF5B是翻译的限制因素。在THP1哺乳动物细胞的血清饥饿中，eIF5B水平的增加导致eIF5B与tRNA- Met(i)复合物的增加。此外，在这些条件下观察到真核起始因子2 α的磷酸化增加，该翻译因子招募启动物tRNA- Met(i)进行一般翻译。重要的是，我们发现eIF5B是G0和G0样状态的拮抗剂，因为eIF5B的缺失会减少G0样、未成熟卵母细胞的成熟，并加速血清饥饿THP1细胞的早期G0停滞。在血清饥饿的THP1细胞中，eIF5B过表达促进G0样未成熟卵母细胞的成熟，并导致细胞死亡（G0的替代）。这些数据揭示了翻译因子在调节特定细胞周期转变和发育阶段中的关键作用。
Proliferation arrest and distinct developmental stages alter and decrease general translation yet maintain ongoing translation. The factors that support translation in these conditions remain to be characterized. We investigated an altered translation factor in three cell states considered to have reduced general translation: immature Xenopus laevis oocytes, mouse ES cells, and the transition state of proliferating mammalian cells to quiescence (G0) upon growth- factor deprivation. Our data reveal a transient increase of eukaryotic translation initiation factor 5B (eIF5B), the eukaryotic ortholog of bacterial initiation factor IF2, in these conditions. eIF5B promotes 60S ribosome subunit joining and pre- 40S subunit proofreading. eIF5B has also been shown to promote the translation of viral and stress- related mRNAs and can contribute indirectly to supporting or stabilizing initiator methionyl tRNA (tRNA- Met(i)) association with the ribosome. We find that eIF5B is a limiting factor for translation in these three conditions. The increased eIF5B levels lead to increased eIF5B complexes with tRNA- Met(i) upon serum starvation of THP1 mammalian cells. In addition, increased phosphorylation of eukaryotic initiation factor 2 alpha, the translation factor that recruits initiator tRNA- Met(i) for general translation, is observed in these conditions. Importantly, we find that eIF5B is an antagonist of G0 and G0- like states, as eIF5B depletion reduces maturation of G0- like, immature oocytes and hastens early G0 arrest in serumstarved THP1 cells. Consistently, eIF5B overexpression promotes maturation of G0- like immature oocytes and causes cell death, an alternative to G0, in serum- starved THP1 cells. These data reveal a critical role for a translation factor that regulates specific cell- cycle transition and developmental stages.