Phosphorylation status determines the opposing functions of Smad2/Smad3 as STAT3 cofactors in TH17 differentiation

Nat Commun. 2015 Jul 21;6:7600. doi: 10.1038/ncomms8600.

Abstract

Transforming growth factor-β (TGF-β) and interleukin-6 (IL-6) are the pivotal cytokines to induce IL-17-producing CD4(+) T helper cells (TH17); yet their signalling network remains largely unknown. Here we show that the highly homologous TGF-β receptor-regulated Smads (R-Smads): Smad2 and Smad3 oppositely modify STAT3-induced transcription of IL-17A and retinoic acid receptor-related orphan nuclear receptor, RORγt encoded by Rorc, by acting as a co-activator and co-repressor of STAT3, respectively. Smad2 linker phosphorylated by extracellular signal-regulated kinase (ERK) at the serine 255 residue interacts with STAT3 and p300 to transactivate, whereas carboxy-terminal unphosphorylated Smad3 interacts with STAT3 and protein inhibitor of activated STAT3 (PIAS3) to repress the Rorc and Il17a genes. Our work uncovers carboxy-terminal phosphorylation-independent noncanonical R-Smad-STAT3 signalling network in TH17 differentiation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Arthritis, Experimental / immunology
  • Arthritis, Experimental / metabolism
  • Cell Differentiation*
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Interleukin-17 / metabolism
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Nuclear Receptor Subfamily 1, Group F, Member 3 / metabolism
  • Phosphorylation
  • STAT3 Transcription Factor / metabolism*
  • Smad2 Protein / metabolism*
  • Smad3 Protein / metabolism*
  • Th17 Cells*

Substances

  • Interleukin-17
  • Nuclear Receptor Subfamily 1, Group F, Member 3
  • Rorc protein, mouse
  • STAT3 Transcription Factor
  • Smad2 Protein
  • Smad2 protein, mouse
  • Smad3 Protein
  • Smad3 protein, mouse
  • Stat3 protein, mouse
  • Extracellular Signal-Regulated MAP Kinases