IRE1α RNaseのアロステリック抑制は,エンドプラズマ網膜のストレス中に細胞の生存能力と機能を保ちます
Rajarshi Ghosh1, Likun Wang2, Eric S Wang3
1Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Pathology, University of California, San Francisco, San Francisco, CA 94143, USA; Diabetes Center, University of California, San Francisco, San Francisco, CA 94143, USA; Lung Biology Center, University of California, San Francisco, San Francisco, CA 94143, USA; California Institute for Quantitative Biosciences, University of California, San Francisco, San Francisco, CA 94143, USA.
Cell
|July 15, 2014
まとめ
KIRAsと呼ばれる小さな分子は,エンドプラズマ網膜 (ER) ストレスに関与するタンパク質,IRE1αを阻害することができます. この抑制は,細胞の生存を促進し,様々な組織におけるERストレスに関連する変性に対して保護します.
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
- バイオケミストリー バイオケミストリー
背景:
- エンドプラズマ網膜 (ER) のストレス反応は,適応とアポトーシスの間の細胞運命を決定するタンパク質 IRE1α を含む.
- IRE1αの活性化には,ホモオリゴメリゼーションとオートフォスフォリレーションが含まれ,XBP1 mRNAが適応のためにスプライシングされる.
- 重度のERストレス下では,IRE1αの拡張された活動は,追加のmRNAを分裂することによってアポトーシスを促進します.
研究 の 目的:
- IRE1αのRNase機能を阻害することによって,その活性を調節する小分子を開発する.
- これらの阻害剤の治療の可能性を,ERストレス関連疾患の臨床前モデルで調査する.
主な方法:
- ATPと競合するIRE1αキナーゼ阻害RNase減衰剤 (KIRA) の設計と合成.
- IRE1αを阻害するKIRAの有効性のインビトロおよびインビボ評価.
- KIRA6の評価は,網膜変性およびアキタ糖尿病マウスのラットモデルで行われました.
主要な成果:
- KIRAsは,オリゴマーを破壊することによって,IRE1αをアロステリックに抑制するために開発されました.
- 最適化されたKIRA6は,IRE1αのインビボ抑制を実証し,ERストレス下での細胞生存を促進しました.
- KIRA6は,網膜変性モデルにおける光受容体活性を保ち,糖尿病マウスにおける臓β細胞を保護した.
結論:
- IRE1α活動は,ERストレス中の細胞運命を決定する重要な決定因子です.
- KIRA6のような小分子阻害剤は,ERストレス誘発の細胞変性緩和のための潜在的な治療戦略を提供します.
- KIRAsでIRE1αをターゲットにすることは,網膜変性や糖尿病などの疾患の治療に有望であることが示されています.
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