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Glucose dissociates DDX21 dimers to regulate mRNA splicing and tissue differentiation
Cell ( IF 45.5 ) Pub Date : 2023-01-05 , DOI: 10.1016/j.cell.2022.12.004 Weili Miao 1 , Douglas F Porter 1 , Vanessa Lopez-Pajares 1 , Zurab Siprashvili 1 , Robin M Meyers 1 , Yunhao Bai 2 , Duy T Nguyen 1 , Lisa A Ko 1 , Brian J Zarnegar 1 , Ian D Ferguson 3 , Matthew M Mills 4 , Christie E Jilly-Rehak 4 , Cheng-Guo Wu 5 , Yen-Yu Yang 6 , Jordan M Meyers 1 , Audrey W Hong 1 , David L Reynolds 1 , Muthukumar Ramanathan 2 , Shiying Tao 1 , Sizun Jiang 7 , Ryan A Flynn 8 , Yinsheng Wang 6 , Garry P Nolan 2 , Paul A Khavari 9
Cell ( IF 45.5 ) Pub Date : 2023-01-05 , DOI: 10.1016/j.cell.2022.12.004 Weili Miao 1 , Douglas F Porter 1 , Vanessa Lopez-Pajares 1 , Zurab Siprashvili 1 , Robin M Meyers 1 , Yunhao Bai 2 , Duy T Nguyen 1 , Lisa A Ko 1 , Brian J Zarnegar 1 , Ian D Ferguson 3 , Matthew M Mills 4 , Christie E Jilly-Rehak 4 , Cheng-Guo Wu 5 , Yen-Yu Yang 6 , Jordan M Meyers 1 , Audrey W Hong 1 , David L Reynolds 1 , Muthukumar Ramanathan 2 , Shiying Tao 1 , Sizun Jiang 7 , Ryan A Flynn 8 , Yinsheng Wang 6 , Garry P Nolan 2 , Paul A Khavari 9
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Glucose is a universal bioenergy source; however, its role in controlling protein interactions is unappreciated, as are its actions during differentiation-associated intracellular glucose elevation. Azido-glucose click chemistry identified glucose binding to a variety of RNA binding proteins (RBPs), including the DDX21 RNA helicase, which was found to be essential for epidermal differentiation. Glucose bound the ATP-binding domain of DDX21, altering protein conformation, inhibiting helicase activity, and dissociating DDX21 dimers. Glucose elevation during differentiation was associated with DDX21 re-localization from the nucleolus to the nucleoplasm where DDX21 assembled into larger protein complexes containing RNA splicing factors. DDX21 localized to specific SCUGSDGC motif in mRNA introns in a glucose-dependent manner and promoted the splicing of key pro-differentiation genes, including , , , and . These findings uncover a biochemical mechanism of action for glucose in modulating the dimerization and function of an RNA helicase essential for tissue differentiation.
中文翻译：
葡萄糖解离 DDX21 二聚体来调节 mRNA 剪接和组织分化
葡萄糖是一种通用的生物能源；然而，它在控制蛋白质相互作用方面的作用尚未得到重视，它在分化相关的细胞内葡萄糖升高过程中的作用也是如此。叠氮-葡萄糖点击化学鉴定出葡萄糖与多种 RNA 结合蛋白 (RBP) 结合，包括 DDX21 RNA 解旋酶，该酶被发现对表皮分化至关重要。葡萄糖结合 DDX21 的 ATP 结合结构域，改变蛋白质构象，抑制解旋酶活性，并解离 DDX21 二聚体。分化过程中的葡萄糖升高与 DDX21 从核仁重新定位到核质相关，在核质中 DDX21 组装成含有 RNA 剪接因子的更大蛋白质复合物。 DDX21 以葡萄糖依赖性方式定位于 mRNA 内含子中的特定 SCUGSDGC 基序，并促进关键促分化基因的剪接，包括 、 、 和 。这些发现揭示了葡萄糖调节组织分化所必需的 RNA 解旋酶的二聚化和功能的生化机制。
更新日期：2023-01-05
中文翻译：
葡萄糖解离 DDX21 二聚体来调节 mRNA 剪接和组织分化
葡萄糖是一种通用的生物能源；然而，它在控制蛋白质相互作用方面的作用尚未得到重视，它在分化相关的细胞内葡萄糖升高过程中的作用也是如此。叠氮-葡萄糖点击化学鉴定出葡萄糖与多种 RNA 结合蛋白 (RBP) 结合，包括 DDX21 RNA 解旋酶，该酶被发现对表皮分化至关重要。葡萄糖结合 DDX21 的 ATP 结合结构域，改变蛋白质构象，抑制解旋酶活性，并解离 DDX21 二聚体。分化过程中的葡萄糖升高与 DDX21 从核仁重新定位到核质相关，在核质中 DDX21 组装成含有 RNA 剪接因子的更大蛋白质复合物。 DDX21 以葡萄糖依赖性方式定位于 mRNA 内含子中的特定 SCUGSDGC 基序，并促进关键促分化基因的剪接，包括 、 、 和 。这些发现揭示了葡萄糖调节组织分化所必需的 RNA 解旋酶的二聚化和功能的生化机制。
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