IRE1のシグナリングは,展開されたタンパク質応答の過程で細胞の運命を左右します
Jonathan H Lin1, Han Li, Douglas Yasumura
1Howard Hughes Medical Institute, University of California at San Francisco, San Francisco, CA 94158, USA. Jonathan.Lin@ucsf.edu
Science (New York, N.Y.)
|November 10, 2007
まとめ
持続的な内プラズマ網膜 (ER) ストレスがPERKシグナル伝達を促進し,細胞死を促進します. IRE1のシグナル伝達を維持すると,細胞生存が向上し,展開タンパク質応答 (UPR) の重要なメカニズムが明らかになる.
科学分野:
- 細胞生物学 細胞生物学
- ERストレスの分子メカニズム
- 展開タンパク質応答 (UPR) 信号伝達経路
背景:
- エンドプラズマ網膜 (ER) のストレスは,誤った折りたたまれたタンパク質を管理するために,展開されたタンパク質応答 (UPR) を誘発します.
- UPRは,細胞生存またはアポトーシスを促進できるIRE1,PERK,ATF6の3つの主要ブランチで構成されています.
- UPR信号が細胞の運命を決定するメカニズム (生存とアポトーシス) は不明である.
研究 の 目的:
- 持続的なERストレス下において,UPRがプロ生存およびプロアポプトシス信号を統合する方法を調査する.
- 細胞の運命決定におけるUPRブランチシグナリングの持続時間の役割を決定する.
- レチニティス・ピグメント症の細胞および動物モデルにおけるこれらの発見の関連性を調査する.
主な方法:
- 持続的なERストレス下にあるヒト細胞におけるUPRブランチ活動 (IRE1,PERK,ATF6) の分析.
- IRE1のシグナル伝達期間を操作して,細胞生存への影響を評価する.
- 変異したロドプシンを持つ動物モデルからの光受容体細胞での発見の検証.
主要な成果:
- 持続的なERストレスにより,IRE1とATF6の活性が弱まりました.
- 翻訳阻害とChop誘導を含むPERKシグナリングは持続していました.
- IRE1の活性を人工的に維持することで,細胞生存が促進された.
- 重要な発見は, retinitis pigmentosaの動物モデルで再現されました.
結論:
- UPRブランクシグナリングの持続時間は,ERストレス後の細胞運命を決定するために重要です.
- 持続的なPERKシグナリングは細胞死に貢献し,持続的なIRE1シグナリングは生存を促進します.
- これらの発見は,レチニティス・ピグメント症に関連したERストレス誘発細胞死メカニズムに関する洞察を提供します.
関連する概念動画
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