Upf1のリン酸化は,ナンセンス媒介のmRNAの分解の間に翻訳抑制を誘発する

Olaf Isken¹, Yoon Ki Kim, Nao Hosoda

¹Department of Biochemistry and Biophysics, School of Medicine and Dentistry, 601 Elmwood Avenue, Box 712, University of Rochester, Rochester, NY 14642, USA.

Cell

|April 22, 2008

まとめ

無意味な媒介によるmRNA衰退 (NMD) は,リン酸化Upf1を阻害する翻訳開始因子eIF3.3を含む. これは,さらなる翻訳を防止し,転写を劣化のためにマークします.

科学分野:

分子生物学は分子生物学である.
細胞生物学細胞生物学
RNA 生物学 RNA 生物学

背景:

無意味な媒介によるmRNA衰退 (NMD) は,異常なmRNAを早期停止コドンで分解する監視経路です.
NMDは,通常,パイオニア翻訳ラウンドの間に,エクソン結合複合体 (EJC) の上流で翻訳終結を必要とします.
EJC関連キナーゼによるUpf1のリン酸化は,NMDの活性化における重要なイベントです.

研究の目的:

NMD.でフォスフォ-Upf1が機能する分子メカニズムを解明する.
フォスフォ-Upf1と翻訳開始因子の相互作用を調査する.
翻訳抑制が,NMD.におけるmRNAの分解とどのように結びついているかを理解する.

主な方法:

タンパク質とタンパク質の相互作用を研究するための生化学的測定法.
哺乳類の細胞抽出物を用いたインビトロ翻訳試験.
NMD標的と非標的のトランスクリプトのmRNA分解率の分析.
NMDにおけるeIF3とCRPV IRESの役割を調査する.

主要な成果:

Phospho-Upf1は,翻訳開始因子eIF3.3と直接相互作用する.
Phospho-Upf1は,eIF3.3に依存する80S翻訳開始複合体の形成を阻害する.
CrPV IRESを通じてeIF3から独立して翻訳を開始するトランスクリプトの場合は,NMDの効率が低下します.
これは,mRNAの劣化に翻訳抑制が先行する重要なステップを特定します.

結論:

Phospho-Upf1は,eIF3.3を阻害することによって,翻訳開始の抑制剤として作用します.
この阻害は,先駆者翻訳複合体を翻訳的に抑圧されたRNPに変換し,NMDを容易にします.
発見は,NMD.のmRNA衰退と翻訳抑制を結びつける保存されたメカニズムを明らかにしています.

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