Glucose dissociates DDX21 dimers to regulate mRNA splicing and tissue differentiation

作者：Weili Miao, Douglas F. Porter, Vanessa Lopez-Pajares, Zurab Siprashvili, Robin M. Meyers, Yunhao Bai, Duy T. Nguyen, Lisa A. Ko, Brian Zarnegar, Ian Ferguson, Matthew M. Mills, C. E. Jilly‐Rehak, Cheng-Guo Wu, Yen‐Yu Yang, Jordan M. Meyers, Audrey W. Hong, David L. Reynolds, Muthukumar Ramanathan, Shiying Tao, Sizun Jiang, Ryan A. Flynn, Yinsheng Wang, Garry P. Nolan, Paul A. Khavari · 发表于：Cell · 年份：2023 · DOI：10.1016/j.cell.2022.12.004 · 被引用次数：72 · 研究领域：RNA Research and Splicing、RNA modifications and cancer、Neurogenetic and Muscular Disorders Research

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 GRHL3, KLF4, OVOL1, and RBPJ. These findings uncover a biochemical mechanism of action for glucose in modulating the dimerization and function of an RNA helicase essential for tissue differentiation.