Niche signalling regulates eIF3d1 phosphorylation to promote distinct modes of translation initiation in stem and differentiating cells
Niche signalling regulates eIF3d1 phosphorylation to promote distinct modes of translation initiation in stem and differentiating cells
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Niche 信号调节 eIF3d1 磷酸化以促进干细胞和分化细胞中不同的翻译起始模式
DOI：
10.1101/2023.12.15.571284
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发表时间：
2023
期刊：
影响因子：
--
通讯作者：
Wang R
中科院分区：
文献类型：
--
作者：
Wang R
干细胞在成体细胞中具有产生不同身份的细胞的独特能力。要做到这一点，它们必须改变基因表达以响应环境信号。许多工作都集中在如何调节转录来实现这些变化，然而在许多细胞类型中，转录本和蛋白质的相关性很差，这表明转录后调节是重要的。为了评估翻译控制如何影响干细胞的命运，我们使用果蝇睾丸作为模型。睾丸小生境分泌配体以激活两种干细胞群体中的JAK/STAT途径，即生殖系干细胞（GSC）和体细胞囊肿干细胞（CySC）。我们发现，全球翻译率高，在CySC和分化过程中下降，JAK/STAT信号调节翻译。为了确定翻译是如何被调节的，我们敲低了翻译起始因子，发现帽结合复合物eIF 4F在分化细胞中被激活，但在CySC中是自我更新所特别需要的，作用于JAK/STAT活性的下游。此外，我们确定eIF 3d 1作为CySC命运的关键调节因子，并表明其磷酸化对维持CySC自我更新至关重要。我们进一步表明，酪蛋白激酶II，控制eIF 3d 1磷酸化，足以恢复在JAK/STAT的情况下，CySC的功能。我们提出了一个模型，其中小生境信号调节一个特定的翻译程序，其中只有一些mRNA的翻译，通过调节eIF 3d磷酸化。我们确定的机制允许干细胞在翻译模式之间切换，在转录之上添加一层调控，并为细胞提供在接受外部刺激时快速改变基因表达的能力。
Stem cells have the unique ability among adult cells to give rise to cells of different identities. To do so, they must change gene expression in response to environmental signals. Much work has focused on how transcription is regulated to achieve these changes, however in many cell types, transcripts and proteins correlate poorly, indicating that post-transcriptional regulation is important. To assess how translational control can influence stem cell fate, we use the Drosophila testis as a model. The testis niche secretes a ligand to activate the JAK/STAT pathway in two stem cell populations, germline stem cells (GSCs) and somatic cyst stem cells (CySCs). We find that global translation rates are high in CySCs and decrease during differentiation, and that JAK/STAT signalling regulates translation. To determine how translation was regulated, we knocked down translation initiation factors and found that the cap binding complex, eIF4F, is dispensable in differentiating cells, but is specifically required in CySCs for self-renewal, acting downstream of JAK/STAT activity. Moreover, we identify eIF3d1 as a key regulator of CySC fate, and show that its phosphorylation is critical to maintain CySC self-renewal. We further show that Casein Kinase II, which controls eIF3d1 phosphorylation, is sufficient to restore CySC function in the absence of JAK/STAT. We propose a model in which niche signals regulate a specific translation programme in which only some mRNAs are translated, through regulation of eIF3d phosphorylation. The mechanism we identify allows stem cells to switch between modes of translation, adding a layer of regulation on top of transcription and providing cells with the ability to rapidly change gene expression upon receiving external stimuli.
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影响因子：
2.7
作者：
Fabrizio, JJ;Boyle, M;DiNardo, S
通讯作者：
DiNardo, S
影响因子：
56.9
作者：
Brunn, GJ;Hudson, CC;Abraham, RT
通讯作者：
Abraham, RT
影响因子：
56.9
作者：
LIN, TA;KONG, XM;LAWRENCE, JC
通讯作者：
LAWRENCE, JC
果蝇蜕皮激素依赖性神经元重塑过程中翻译起始因子途径的差异要求。
影响因子：
8.8
作者：
Sandra Rode;Henrike Ohm;L. Anhäuser;Marina Wagner;M. Rosing;Xiaobing Deng;O. Sin;Sebastian A. Leidel;E. Storkebaum;A. Rentmeister;Sijun Zhu;Sebastian Rumpf
通讯作者：
Sebastian Rumpf
影响因子：
56.9
作者：
Querido, Jailson Brito;Sokabe, Masaaki;Ramakrishnan, V
通讯作者：
Ramakrishnan, V