Reversing SKI-SMAD4-mediated suppression is essential for T <subscript>H</subscript> 17 cell differentiation.
In: Nature, Jg. 551 (2017-11-02), Heft 7678, S. 105-109
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Zugriff:
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.
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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 |
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