Glucose dissociates DDX21 dimers to regulate mRNA splicing and tissue differentiation
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
Abstract
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.