ラグレーター-ラグ複合体は,mTORC1をリソソーム表面に標的にし,アミノ酸によって活性化するために必要である
Yasemin Sancak1, Liron Bar-Peled, Roberto Zoncu
1Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, MA 02142, USA.
Cell
|April 13, 2010
まとめ
アミノ酸は,mTORC1経路に信号を送り,そのトランスロケーションをリソソーム膜に誘導する. この動きは,Rag GTPasesとRagulator複合体によって媒介され,成長の調節に不可欠であり,病気でしばしば混乱します.
科学分野:
- 細胞生物学 細胞生物学
- 分子生物学は分子生物学である.
- バイオケミストリー バイオケミストリー
背景:
- ラパミシン複合体1 (mTORC1) キナーゼの機械的標的は,栄養素や成長因子に反応して細胞の成長を調節する.
- mTORC1シグナリングの調節不全は,がんや代謝障害を含む様々な疾患に起因しています.
- Rag GTPasesはmTORC1と相互作用することが知られており,アミノ酸シグナル伝達を媒介することが提案されています.
研究 の 目的:
- アミノ酸がmTORC1.1.を活性化するメカニズムを解明する.
- アミノ酸センシングとmTORC1の調節に関与する分子プレーヤーを特定する.
- mTORC1の活性化におけるリゾソームの局所化の役割を調査する.
主な方法:
- 免疫光顕微鏡でmTORC1の局所化を追跡する.
- コイムノプレシピテーションアッセイは,タンパク質の相互作用を研究するためのものです.
- 遺伝子操作 (遺伝子ノックアウト/ノックダウン) で,Rag GTPasesとRagulatorの構成要素の機能を評価する.
- mTORC1キナーゼ活性を測定するための生化学分析.
主要な成果:
- アミノ酸刺激により,mTORC1がリゾソーム膜に転位する.
- Ragulator (MAPKSP1, ROBLD3, c11orf59) と呼ばれる新しい複合体は,Rag GTPasesと相互作用し,それらをリソソームに勧誘する.
- ラグレーターは,アミノ酸誘発 mTORC1 の活性化に不可欠です.
- mTORC1がリソソーム膜に定着すると,その経路はアミノ酸の可用性に対して無感となり,Rag/Ragulatorの機能とは無関係になります.
結論:
- mTORC1のラグ・レギュレータによるリクルートメントは,アミノ酸がmTORC1.1へのシグナルを送信する際の重要なステップです.
- このメカニズムは,栄養素感知と成長制御のための中心的なハブとしてのリゾソームを強調します.
- この経路の理解は,mTORC1の調節不良に関連した疾患の潜在的な治療目標を提供します.
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