mRNAメチレーションは,IL-7/STAT5/SOCS経路を標的としてT細胞ホメオスタシスを制御する
Hua-Bing Li1, Jiyu Tong1,2, Shu Zhu1
1Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
Nature
|August 10, 2017
まとめ
この研究は,T細胞生物学におけるN6-メチラデノシン (m6A) RNA改変のインビボの役割を明らかにしている. T細胞のm6AライターのMETTL3を削除すると,免疫細胞の恒常性と分化が妨げられます.
科学分野:
- 免疫学
- エピジェネティクス
- 分子生物学
背景:
- N6-メチラデノシン (m6A) は,mRNA代謝をインビトロで影響する最も一般的なmRNA変異である.
- 成人哺乳類の細胞,特にT細胞における in vivo 生理学的機能はほとんど不明である.
研究 の 目的:
- 哺乳類のT細胞機能におけるm6A"ライター"タンパク質METTL3のインビヴォの役割を調査する.
- m6AがT細胞ホメオスタシスと分化に影響を与えるメカニズムを解明する.
主な方法:
- マウスT細胞のMETTL3遺伝子の削除
- Mettl3欠乏性T細胞をリンパパニアのマウスに移植する.
- T細胞ホメオスタシス,分化,遺伝子発現,mRNAの衰退率の分析
主要な成果:
- Mettl3欠乏したナイブT細胞は拡大して分化できず,移植モデルでは大腸炎を予防した.
- SOCSファミリーのmRNAのm6A変異は,Mettl3欠乏性T細胞の衰退を遅らせ,発現を増加させた.
- 増加したSOCSはIL-7媒介のSTAT5活性化を阻害し,T細胞の増殖と分化を阻害した.
結論:
- METTL3経由のm6A変異は,T細胞の恒常性と微分化を維持するために不可欠である.
- m6Aは,IL-7のシグナル伝達に反応して,SOCS遺伝子の誘導可能なmRNAの分解を調節する.
- この研究は,T細胞の生物学と病原性におけるm6Aの新しいメカニズムを発見した.
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