The citrullinating enzyme PADI4 governs progenitor cell proliferation and translation in developing hair follicles

Sci Adv. 2025 Sep 12;11(37):eadx4511. doi: 10.1126/sciadv.adx4511. Epub 2025 Sep 12.

Abstract

Posttranslational protein modifications have emerged as a mechanism regulating progenitor cell state transitions during tissue formation. Herein, we exploit the stereotyped hair follicle development to delineate the function of PADI4, an enzyme converting peptidylarginine to citrulline. Single-cell sequencing places Padi4 in both progenitor and differentiated hair lineage cells and indicates that PADI4 acts to repress transcription during hair follicle development. We establish PADI4 as a negative regulator of proliferation, acting on LEF1-positive hair shaft committed progenitor cells. Mechanistically, PADI4 citrullinates proteins associated with mRNA processing and ribosomal biogenesis, and lack of PADI4 promotes protein synthesis and ribosomal RNA transcription in vivo. Characterizing key translational effectors, we demonstrate that PADI4 citrullinates the translational repressor 4E-BP1 and reveal a cross-talk between PADI4 activity and 4E-BP1 phosphorylation. This work sheds light on how posttranslational modifications affect progenitor cell states and tissue formation.

MeSH terms

  • Animals
  • Cell Differentiation
  • Cell Proliferation*
  • Citrullination
  • Hair Follicle* / cytology
  • Hair Follicle* / growth & development
  • Hair Follicle* / metabolism
  • Mice
  • Phosphorylation
  • Protein Biosynthesis*
  • Protein Processing, Post-Translational
  • Protein-Arginine Deiminase Type 4* / genetics
  • Protein-Arginine Deiminase Type 4* / metabolism
  • Stem Cells* / cytology
  • Stem Cells* / metabolism

Substances

  • Protein-Arginine Deiminase Type 4
  • peptidylarginine deiminase 4, mouse