Glucose dissociates DDX21 dimers to regulate mRNA splicing and tissue differentiation

• DOI: 10.1016/j.cell.2022.12.004
• Publication Date: 2023-01-05T15:39:27Z
• Authors: Weili Miao; Douglas F. Porter; Vanessa Lopez-Paj...; Zurab Siprashvili; Robin M. Meyers; Yunhao Bai; Duy T. Nguyen; Lisa A. Ko; Brian J. Zarnegar; Ian D. Ferguson; Matthew M. Mills; Christie E. Jilly...; Cheng-Guo Wu; Yen-Yu Yang; Jordan M. Meyers; Audrey W. Hong; David L. Reynolds; Muthukumar Ramana...; Shiying Tao; Sizun Jiang; Ryan A. Flynn; Yinsheng Wang; Garry P. Nolan; Paul A. Khavari
• Keywords: Cell Nucleus; DEAD-box RNA Helicases; Keratinocytes; 0301 basic medicine; 03 medical and health sciences; Glucose; Humans; RNA, Messenger; Cell Nucleolus

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.