SKI-SMAD4による抑制を逆転させることは,TH17細胞の分化に不可欠である
Song Zhang1,2, Motoki Takaku3, Liyun Zou1,2
1Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, North Carolina 27599, USA.
Nature
|October 27, 2017
まとめ
変換成長因子β (TGFβ) は,RORγtのSKI-SMAD4抑制を逆転させることで,Tヘルパー17 (TH17) 細胞の分化を可能にします. これはTH17細胞を制御する重要なメカニズムを明らかにし,SKI-SMAD4軸を治療標的として特定します.
科学分野:
- 免疫学
- 細胞・分子生物学
- 病気 の 分子 機構
背景:
- Tヘルパー17 (TH17) 細胞は宿主防御,炎症,自己免疫に不可欠である.
- 変換成長因子β (TGFβ) は,TH17細胞の分化に不可欠であり,しばしばインタールイキン-6と併用されます.
- TGFβがTH17の分化を促進する正確な分子機構は不明のままである.
研究 の 目的:
- TGFβがTH17細胞の分化を促進するメカニズムを解明する.
- RORγt発現とTH17の分化におけるSKI-SMAD4複合体の役割を調査する.
- TH17媒介疾患に対する潜在的な治療標的を特定する.
主な方法:
- ワイルド型とSMAD4欠乏型T細胞におけるT細胞の分化分析
- RORγt発現とTH17の微分化による子宮外SMAD4またはSKI発現の調査.
- タンパク質の相互作用 (SMAD4とSKI) を特定するためのプロテオミック分析.
- ヒストンのアセチル化によるRorc場所の評価
主要な成果:
- SMAD4欠乏性T細胞は,RORγtに依存して,TH17細胞にTGFβシグナル伝達から独立して分化する.
- TGFβは,SKI- SMAD4媒介による網膜酸受容体関連孤児受容体 γt (RORγt) の発現を逆転させます.
- SMAD4は,TGFβ刺激により分解される転写抑制体SKIと相互作用する.
- SKIは,RorcロカスとTH17の微分化をSMAD4を通じて制御する.
結論:
- TGFβは,SKI-SMAD4複合体を破壊することによって,TH17細胞の分化を可能にし,それによってRORγt抑制を逆転させます.
- SKI-SMAD4軸は,RORγt発現とTH17細胞の微分化の重要なレギュラーである.
- SKI-SMAD4軸をターゲットにすることで,TH17細胞によって引き起こされる自己免疫性および炎症性疾患に対する潜在的な治療戦略が提供されます.
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