Human Keratinocyte Differentiation Requires Translational Control by the eIF2α Kinase GCN2.
Human Keratinocyte Differentiation Requires Translational Control by the eIF2α Kinase GCN2.
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DOI：
10.1016/j.jid.2017.04.029
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发表时间：
2017-09
期刊：
影响因子：
--
通讯作者：
Spandau DF
中科院分区：
文献类型：
--
作者：
Collier AE;Wek RC;Spandau DF
角质形成细胞的适当和顺序分化对于人表皮的所有功能是必不可少的。虽然转录调控已被证明是角质形成细胞分化的重要，很少有人知道的翻译控制的作用。调节翻译的一个关键机制是通过eIF2 α亚基的磷酸化。一个不同的eIF2α激酶家族在整合应激反应中发挥作用，抑制一般蛋白质合成，同时优先翻译参与应激缓解的选定mRNA。在这里，我们证明了通过eIF2α磷酸化的翻译控制是正常角质形成细胞分化所必需的。多聚核糖体的分析表明，关键的分化基因，包括外皮蛋白，在分化过程中绑定到重多聚核糖体，尽管一般蛋白质合成减少。GCN 2蛋白激酶诱导的eIF2α磷酸化促进角质形成细胞分化过程中的翻译控制和分化特异性蛋白表达。此外，在器官型皮肤培养中，GCN 2的缺失阻碍了翻译控制、正常表皮分化和分化基因表达。这些发现强调了GCN 2磷酸化eIF2α和翻译控制在完整人类表皮形成中的一个先前未知的功能。
Appropriate and sequential differentiation of keratinocytes is essential for all functions of the human epidermis. While transcriptional regulation has proven to be important for keratinocyte differentiation, little is known about the role of translational control. A key mechanism for modulating translation is through phosphorylation of the α subunit of eIF2. A family of different eIF2α kinases function in the integrative stress response to inhibit general protein synthesis coincident with preferential translation of select mRNAs that participate in stress alleviation. Here we demonstrate that translational control through eIF2α phosphorylation is required for normal keratinocyte differentiation. Analyses of polysome profiles revealed that key differentiation genes, including involucrin, are bound to heavy polysomes during differentiation, despite decreased general protein synthesis. Induced eIF2α phosphorylation by the GCN2 protein kinase facilitated translational control and differentiation-specific protein expression during keratinocyte differentiation. Furthermore, loss of GCN2 thwarted translational control, normal epidermal differentiation, and differentiation gene expression in organotypic skin culture. These findings underscore a previously unknown function for GCN2 phosphorylation of eIF2α and translational control in the formation of an intact human epidermis.
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