title: The deubiquitinase CYLD targets Smad7 protein to regulate transforming growth factor β (TGF-β) signaling and the development of regulatory T cells.
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.
authors.affiliation: Laboratory of Host Defenses, NIAID, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Yongge
authors.initials: Y
authors.lastname: Zhao
authors.forename: Angela M
authors.initials: AM
authors.lastname: Thornton
authors.forename: Matthew C
authors.initials: MC
authors.lastname: Kinney
authors.forename: Chi A
authors.initials: CA
authors.lastname: Ma
authors.forename: Jacob J
authors.initials: JJ
authors.lastname: Spinner
authors.forename: Ivan J
authors.initials: IJ
authors.lastname: Fuss
authors.forename: Ethan M
authors.initials: EM
authors.lastname: Shevach
authors.forename: Ashish
authors.initials: A
authors.lastname: Jain
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D003546:Cysteine Endopeptidases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000074749:Deubiquitinating Enzyme CYLD; D051858:Forkhead Transcription Factors / Q000235:genetics; D055786:Gene Knockout Techniques; D006367:HeLa Cells; D006801:Humans; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism; D008198:Lymph Nodes / Q000276:immunology; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects; D051379:Mice; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D015398:Signal Transduction / Q000187:drug effects; D051906:Smad7 Protein / Q000378:metabolism*; D050378:T-Lymphocytes, Regulatory / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism* / Q000494:pharmacology; D054875:Ubiquitination / Q000187:drug effects; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D000099151:MAP Kinase Kinase Kinase 7
chemical_list: D003546:Cysteine Endopeptidases; D000074749:Deubiquitinating Enzyme CYLD; D051858:Forkhead Transcription Factors; D053645:Interleukin-2 Receptor alpha Subunit; D020930:MAP Kinase Kinase Kinases; D051906:Smad7 Protein; D016212:Transforming Growth Factor beta; D048051:p38 Mitogen-Activated Protein Kinases; D000099151:MAP Kinase Kinase Kinase 7; C418974:FOXP3 protein, human; C511601:CYLD protein, mouse