Glucose dissociates DDX21 dimers to regulate mRNA processing and promote epidermal differentiation (RNA-Seq III)

Glucose is an important cellular energy source, however, glucose’s function as a second messenger remains relatively unexplored. Here, we find that glucose binds directly to DDX21 to regulate its function during epidermal differentiation. Specifically, glucose binds to the ATP-binding domain of DDX21 to induce a conformational change and inhibit helicase activity. Glucose binding inhibits the dimerization of DDX21 leading to re-localization from the nucleolus to the nucleoplasm and reassembly of DDX21 into larger protein complexes, increasing its association with splicing factors. This occurs during keratinocyte differentiation, where glucose accumulation is necessary, and results in DDX21 binding to RNA processing proteins and mRNA introns. Consequently, DDX21 regulates the splicing of key differentiation factors and promotes epidermal differentiation in a glucose-dependent manner. These findings reveal a novel mechanism of glucose regulation of cell signaling. Two biological replicates of primary human foreskin keratinocytes were for RNA expression levels and splicing alterations caused by shDDX21 knock-down during differentiation.

葡萄糖是重要的细胞能量来源，但其作为第二信使的功能迄今仍未得到充分探索。本研究发现，葡萄糖可直接结合DDX21，进而在表皮分化过程中调控其功能。具体而言，葡萄糖结合DDX21的ATP结合结构域，诱导其构象改变并抑制解旋酶活性。葡萄糖结合可抑制DDX21的二聚化，使其从核仁重新定位至核质，并促使DDX21组装为更大的蛋白质复合物，增强其与剪接因子的结合互作。该过程发生于葡萄糖积累必不可少的角质形成细胞分化阶段，最终导致DDX21结合RNA加工蛋白与mRNA内含子。因此，DDX21可调控关键分化因子的剪接过程，并以葡萄糖依赖的方式促进表皮分化。本研究发现揭示了葡萄糖调控细胞信号传导的全新机制。本研究设置原代人包皮角质形成细胞的两组生物学重复，以分析分化过程中shDDX21敲低所引发的RNA表达水平变化与剪接异常。