老化によりリボソームの停止が悪化し,コトランスレーション性プロテオスタシスが破壊される

Kevin C Stein¹, Fabián Morales-Polanco¹, Joris van der Lienden¹

¹Department of Biology, Stanford University, Stanford, CA, USA.

Nature

|January 20, 2022

まとめ

細胞のタンパク質の品質管理は老化によって低下し,リボソームのトランスレーション中断が増加する. これは誤った折りたたみのタンパク質の蓄積につながり,老化に関連した衰退に寄与します.

科学分野:

分子生物学
ゲロントロジー
細胞生物学

背景:

細胞のプロテオスタシスは年齢とともに低下し,タンパク質の誤折り疾患に寄与する.
老化がプロテオスタシスを損なうメカニズムは完全に理解されていません.
新生ポリペプチドは,プロテオスタシスネットワークに重大な課題をもたらします.

研究の目的:

老化中の翻訳効率の変化がプロテオスタシスの崩壊に寄与するという仮説を検証する.
リボソームの停止とリボソーム関連品質管理 (RQC) の老化過程における役割を明らかにする.

主な方法:

高齢のCaenorhabditis elegansとSaccharomyces cerevisiaeにおけるトランスレーション延長運動の比較分析
リボソームの停止部位を特定し,多塩基的部位を含む.
熟成酵母におけるRQC基板のクリアランスと集積の評価
酵母変異体におけるリボソームの停止とRQC経路の流れとの相関.

主要な成果:

老化により,リボソームの延伸運動が変化し,酵母と虫の特定の部位でのリボソームの停止が悪化する.
リボソームの停止が増加するとリボソームの衝突が起こり,RQC経路が起動します.
老化した酵母細胞は,RQC基板のクリアランスが低下し,集積が増加します.
寿命が長い酵母変異体では,年齢によるリボソームの停止が減少し,RQCの流れが増加する.
年齢に依存するリボソームの停止を持つ新生ポリペプチドは,C. elegansの年齢に依存するタンパク質集積物で濃縮されています.

結論:

老化中のリボソームの停止が増加すると,RQC経路が圧倒され,新生ポリペプチドの集積が起こります.
このRQCの過負荷は,老化時にタンパク質静止障害と全身的衰退に重大な影響を及ぼします.
翻訳効率とRQCをターゲットにすることは,年齢に関連したプロテオスタシスの低下を緩和するための潜在的な戦略である可能性があります.

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