Glucose dissociates DDX21 dimers to regulate mRNA splicing and tissue differentiation

Cell. 2023 Jan 5;186(1):80-97.e26. doi: 10.1016/j.cell.2022.12.004.


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.

Keywords: DDX21; RNA helicases; glucose; mRNA splicing; tissue differentiation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Cell Nucleolus / metabolism
  • Cell Nucleus / metabolism
  • DEAD-box RNA Helicases* / metabolism
  • Glucose* / metabolism
  • Humans
  • Keratinocytes* / cytology
  • Keratinocytes* / metabolism
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism


  • DEAD-box RNA Helicases
  • RNA, Messenger
  • Glucose
  • DDX21 protein, human