The deubiquitinase CYLD targets Smad7 protein to regulate transforming growth factor β (TGF-β) signaling and the development of regulatory T cells

J Biol Chem. 2011 Nov 25;286(47):40520-30. doi: 10.1074/jbc.M111.292961. Epub 2011 Sep 19.

Abstract

CYLD is a lysine 63-deubiquitinating enzyme that inhibits NF-κB and JNK signaling. Here, we show that CYLD knock-out mice have markedly increased numbers of regulatory T cells (Tregs) in peripheral lymphoid organs but not in the thymus. In vitro stimulation of CYLD-deficient naive T cells with anti-CD3/28 in the presence of TGF-β led to a marked increase in the number of Foxp3-expressing T cells when compared with stimulated naive control CD4(+) cells. Under endogenous conditions, CYLD formed a complex with Smad7 that facilitated CYLD deubiquitination of Smad7 at lysine 360 and 374 residues. Moreover, this site-specific ubiquitination of Smad7 was required for activation of TAK1 and p38 kinases. Finally, knockdown of Smad7 or inhibition of p38 activity in primary T cells impaired Treg differentiation. Together, our results show that CYLD regulates TGF-β signaling function in T cells and the development of Tregs through deubiquitination of Smad7.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • Animals
  • CD4-Positive T-Lymphocytes / cytology
  • CD4-Positive T-Lymphocytes / drug effects
  • CD4-Positive T-Lymphocytes / metabolism
  • Cysteine Endopeptidases / deficiency
  • Cysteine Endopeptidases / genetics
  • Cysteine Endopeptidases / metabolism*
  • Deubiquitinating Enzyme CYLD
  • Forkhead Transcription Factors / genetics
  • Gene Knockout Techniques
  • HeLa Cells
  • Humans
  • Interleukin-2 Receptor alpha Subunit / metabolism
  • Lymph Nodes / immunology
  • MAP Kinase Kinase Kinases / metabolism
  • MAP Kinase Signaling System / drug effects
  • Mice
  • Promoter Regions, Genetic
  • Protein Binding
  • Signal Transduction* / drug effects
  • Smad7 Protein / metabolism*
  • T-Lymphocytes, Regulatory / cytology*
  • T-Lymphocytes, Regulatory / drug effects
  • T-Lymphocytes, Regulatory / metabolism
  • Transforming Growth Factor beta / metabolism*
  • Transforming Growth Factor beta / pharmacology
  • Ubiquitination / drug effects
  • p38 Mitogen-Activated Protein Kinases / metabolism

Substances

  • FOXP3 protein, human
  • Forkhead Transcription Factors
  • Interleukin-2 Receptor alpha Subunit
  • Smad7 Protein
  • Transforming Growth Factor beta
  • p38 Mitogen-Activated Protein Kinases
  • MAP Kinase Kinase Kinases
  • MAP kinase kinase kinase 7
  • CYLD protein, mouse
  • Deubiquitinating Enzyme CYLD
  • Cysteine Endopeptidases