Pumilio directs deadenylation-associated translational repression of the cyclin-dependent kinase 1 activator RGC-32.
Pumilio directs deadenylation-associated translational repression of the cyclin-dependent kinase 1 activator RGC-32.
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DOI：
10.1093/nar/gky038
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发表时间：
2018-04-20
影响因子：
14.9
通讯作者：
West MJ
中科院分区：
文献类型：
--
作者：
Brocard M;Khasnis S;Wood CD;Shannon-Lowe C;West MJ
补体应答基因-32（RGC-32）激活细胞周期蛋白依赖性激酶1，调节细胞周期，并在许多人类肿瘤中解除调节。我们之前表明，在潜伏感染的B细胞中，癌症相关的EB病毒（EBV）通过解除翻译抑制来上调RGC-32的表达。我们现在表明，EBV感染的幼稚原代B细胞也诱导RGC-32蛋白的翻译。在EBV永生化细胞系中，我们发现RGC-32耗竭导致细胞死亡，表明在B细胞存活中起关键作用。在研究EBV感染细胞中RGC-32的翻译调控时，我们发现RGC-32的3′非翻译区（3′UTR）介导了翻译抑制。抑制依赖于一个单一的Pumilio结合元件（PBE）相邻的多聚腺苷酸化信号。该PBE的突变不影响mRNA切割，但导致polyA尾长度增加。与Pumilio依赖的腺苷酸酶募集一致，我们发现在EBV感染的细胞中Pumilio的耗尽增加了RGC-32蛋白表达和polyA尾长。在EBV感染的细胞系中，Pumilio与内源性RGC-32 mRNA结合的程度也与RGC-32蛋白表达相关。我们的数据证明了RGC-32对于EBV永生化B细胞存活的重要性，并鉴定了Pumilio作为RGC-32翻译的关键调节剂。
Response gene to complement-32 (RGC-32) activates cyclin-dependent kinase 1, regulates the cell cycle and is deregulated in many human tumours. We previously showed that RGC-32 expression is upregulated by the cancer-associated Epstein-Barr virus (EBV) in latently infected B cells through the relief of translational repression. We now show that EBV infection of naïve primary B cells also induces RGC-32 protein translation. In EBV-immortalised cell lines, we found that RGC-32 depletion resulted in cell death, indicating a key role in B cell survival. Studying RGC-32 translational control in EBV-infected cells, we found that the RGC-32 3′untranslated region (3′UTR) mediates translational repression. Repression was dependent on a single Pumilio binding element (PBE) adjacent to the polyadenylation signal. Mutation of this PBE did not affect mRNA cleavage, but resulted in increased polyA tail length. Consistent with Pumilio-dependent recruitment of deadenylases, we found that depletion of Pumilio in EBV-infected cells increased RGC-32 protein expression and polyA tail length. The extent of Pumilio binding to the endogenous RGC-32 mRNA in EBV-infected cell lines also correlated with RGC-32 protein expression. Our data demonstrate the importance of RGC-32 for the survival of EBV-immortalised B cells and identify Pumilio as a key regulator of RGC-32 translation.
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影响因子：
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作者：
GREGORY, CD;MURRAY, RJ;EDWARDS, CF;RICKINSON, AB
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影响因子：
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通讯作者：
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影响因子：
5.4
作者：
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通讯作者：
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