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Reversing SKI-SMAD4-mediated suppression is essential for T <subscript>H</subscript> 17 cell differentiation.

Zhang, S ; Takaku, M ; et al.
In: Nature, Jg. 551 (2017-11-02), Heft 7678, S. 105-109
academicJournal

T helper 17 (T H 17) cells are critically involved in host defence, inflammation, and autoimmunity. Transforming growth factor β (TGFβ) is instrumental in T H 17 cell differentiation by cooperating with interleukin-6 (refs 6, 7). Yet, the mechanism by which TGFβ enables T H 17 cell differentiation remains elusive. Here we reveal that TGFβ enables T H 17 cell differentiation by reversing SKI-SMAD4-mediated suppression of the expression of the retinoic acid receptor (RAR)-related orphan receptor γt (RORγt). We found that, unlike wild-type T cells, SMAD4-deficient T cells differentiate into T H 17 cells in the absence of TGFβ signalling in a RORγt-dependent manner. Ectopic SMAD4 expression suppresses RORγt expression and T H 17 cell differentiation of SMAD4-deficient T cells. However, TGFβ neutralizes SMAD4-mediated suppression without affecting SMAD4 binding to the Rorc locus. Proteomic analysis revealed that SMAD4 interacts with SKI, a transcriptional repressor that is degraded upon TGFβ stimulation. SKI controls histone acetylation and deacetylation of the Rorc locus and T H 17 cell differentiation via SMAD4: ectopic SKI expression inhibits H3K9 acetylation of the Rorc locus, Rorc expression, and T H 17 cell differentiation in a SMAD4-dependent manner. Therefore, TGFβ-induced disruption of SKI reverses SKI-SMAD4-mediated suppression of RORγt to enable T H 17 cell differentiation. This study reveals a critical mechanism by which TGFβ controls T H 17 cell differentiation and uncovers the SKI-SMAD4 axis as a potential therapeutic target for treating T H 17-related diseases.

Titel:
Reversing SKI-SMAD4-mediated suppression is essential for T <subscript>H</subscript> 17 cell differentiation.
Autor/in / Beteiligte Person: Zhang, S ; Takaku, M ; Zou, L ; Gu, AD ; Chou, WC ; Zhang, G ; Wu, B ; Kong, Q ; Thomas, SY ; Serody, JS ; Chen, X ; Xu, X ; Wade, PA ; Cook, DN ; Ting, JPY ; Wan, YY
Zeitschrift: Nature, Jg. 551 (2017-11-02), Heft 7678, S. 105-109
Veröffentlichung: Basingstoke : Nature Publishing Group ; <i>Original Publication</i>: London, Macmillan Journals ltd., 2017
Medientyp: academicJournal
ISSN: 1476-4687 (electronic)
DOI: 10.1038/nature24283
Schlagwort:
  • Animals
  • Female
  • Gene Deletion
  • Humans
  • Interleukin-6 metabolism
  • Male
  • Mice
  • Multiprotein Complexes chemistry
  • Multiprotein Complexes metabolism
  • Nuclear Receptor Subfamily 1, Group F, Member 3 deficiency
  • Nuclear Receptor Subfamily 1, Group F, Member 3 genetics
  • Nuclear Receptor Subfamily 1, Group F, Member 3 metabolism
  • Receptors, Transforming Growth Factor beta metabolism
  • Signal Transduction
  • Smad4 Protein deficiency
  • Smad4 Protein genetics
  • Cell Differentiation genetics
  • DNA-Binding Proteins metabolism
  • Proto-Oncogene Proteins metabolism
  • Repressor Proteins metabolism
  • Smad4 Protein metabolism
  • Th17 Cells cytology
  • Th17 Cells metabolism
  • Transforming Growth Factor beta metabolism
Sonstiges:
  • Nachgewiesen in: MEDLINE
  • Sprachen: English
  • Publication Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, N.I.H., Intramural; Research Support, Non-U.S. Gov't
  • Language: English
  • [Nature] 2017 Nov 02; Vol. 551 (7678), pp. 105-109. <i>Date of Electronic Publication: </i>2017 Oct 25.
  • MeSH Terms: Cell Differentiation* / genetics ; DNA-Binding Proteins / *metabolism ; Proto-Oncogene Proteins / *metabolism ; Repressor Proteins / *metabolism ; Smad4 Protein / *metabolism ; Th17 Cells / *cytology ; Th17 Cells / *metabolism ; Transforming Growth Factor beta / *metabolism ; Animals ; Female ; Gene Deletion ; Humans ; Interleukin-6 / metabolism ; Male ; Mice ; Multiprotein Complexes / chemistry ; Multiprotein Complexes / metabolism ; Nuclear Receptor Subfamily 1, Group F, Member 3 / deficiency ; Nuclear Receptor Subfamily 1, Group F, Member 3 / genetics ; Nuclear Receptor Subfamily 1, Group F, Member 3 / metabolism ; Receptors, Transforming Growth Factor beta / metabolism ; Signal Transduction ; Smad4 Protein / deficiency ; Smad4 Protein / genetics
  • Comments: Comment in: Cell Res. 2018 Feb;28(2):139-140. (PMID: 29219146)
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  • Grant Information: P30 CA016086 United States CA NCI NIH HHS; Z01 ES102025 United States ImNIH Intramural NIH HHS; R01 AI123193 United States AI NIAID NIH HHS; R01 AI029564 United States AI NIAID NIH HHS; AI029564 United States NH NIH HHS; ES102025 United States ImNIH Intramural NIH HHS; R37 AI029564 United States AI NIAID NIH HHS; R01 CA166794 United States CA NCI NIH HHS; ES101965 United States ImNIH Intramural NIH HHS; R56 AI029564 United States AI NIAID NIH HHS; Z01 ES101965 United States ImNIH Intramural NIH HHS; R01 AI097392 United States AI NIAID NIH HHS
  • Substance Nomenclature: 0 (DNA-Binding Proteins) ; 0 (Interleukin-6) ; 0 (Multiprotein Complexes) ; 0 (Nuclear Receptor Subfamily 1, Group F, Member 3) ; 0 (Proto-Oncogene Proteins) ; 0 (Receptors, Transforming Growth Factor beta) ; 0 (Repressor Proteins) ; 0 (Rorc protein, mouse) ; 0 (Ski protein, mouse) ; 0 (Smad4 Protein) ; 0 (Smad4 protein, mouse) ; 0 (Transforming Growth Factor beta)
  • Entry Date(s): Date Created: 20171027 Date Completed: 20180403 Latest Revision: 20210109
  • Update Code: 20240513
  • PubMed Central ID: PMC5743442

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