細胞ホメオスタシスを回復し,アポトシスを抑制するためにTRADDを調節する
Daichao Xu1,2, Heng Zhao1, Minzhi Jin1
1Department of Cell Biology, Harvard Medical School, Boston, MA, USA.
Nature
|September 24, 2020
まとめ
研究者らは,TRADDを細胞死とホメオスタシスの主要な調節因子として特定した. Apt-1のような小分子でTRADDを抑制すると,細胞のバランスが回復し,疾患モデルでの細胞死が防止されます.
科学分野:
- 分子生物学
- 細胞生物学
- 神経科学
背景:
- 細胞死はヒトの病気の特徴であり,しばしば細胞の恒常性障害から生じます.
- 細胞死メカニズムは理解されているが,細胞死抑制後のホメオスタシスの回復は不明である.
- TRADD (TRAFに関連したNF- kB活性化ドメインを含むタンパク質) は,細胞信号伝達経路に関与するアダプタタンパク質です.
研究 の 目的:
- 細胞ホメオスタシスとアポトシスのレギュレータを特定する.
- 細胞のバランスを維持し,細胞死を防ぐためのTRADDの役割を調査する.
- TRADDの治療効果を狙った薬理学的戦略を探求する.
主な方法:
- ベクリン1のK63結合ユビキチネーションとオートファギーの調節におけるTRADDの役割を調査した.
- RIPK1依存アポトーシスとプロテアソームストレス誘発アポトーシスに対するTRADD欠乏の影響を評価した.
- 細胞および動物モデルにおけるTRADD機能を抑制するために,小分子ICCB-19とApt-1を使用した.
主要な成果:
- TRADDはベクリン1のユビキチン化を調節し,細胞死経路に影響を及ぼします.
- TRADD欠乏症はアポトーシスを増加させ,その抑制はアポトーシスを阻害し,ホメオスタシスを回復させます.
- 小分子ICCB-19とApt-1はTRADDに結合し,その機能を阻害し,オートファギーを活性化します.
- TRADDの抑制により,タオパシーのマウスモデルでは,プロテオスタシスが回復し,細胞死が減少した.
結論:
- TRADDは細胞ホメオスタシスとアポトシスの両方の重要な調節剤です.
- ICCB-19またはApt-1によるTRADDの薬理学的阻害は,細胞死とホメオスタシスの障害を特徴とする疾患の治療の可能性を示しています.
- TRADDをターゲットにすると タンパク質病やその他のヒト疾患の治療に 有望な戦略が生まれます
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