保護的なERストレス反応のためのトランボスポンディン依存の経路
Jeffrey M Lynch1, Marjorie Maillet, Davy Vanhoutte
1Department of Pediatrics, Cincinnati Children's Hospital, University of Cincinnati, OH 45247, USA.
Cell
|June 12, 2012
まとめ
トロンボスポンディン (Thbs) タンパク質は,エンドプラズマ網膜 (ER) のストレス反応を強化することによって,心臓損傷から保護します. Thbs4は特に,適応的なERストレスを促進し,ER機能を強化し,疾患の際に心臓を保護します.
科学分野:
- 心血管生物学 心血管生物学
- 細胞のストレス反応は,
- 分子医学は分子医学である.
背景:
- トロンボスポンディン (Thbs) は,組織損傷や改造の部位で上位に調節されるタンパク質です.
- エンドプラズマ網膜 (ER) のストレス反応は,疾患中に活性化され,タンパク質のホメオスタシスを調節します.
- 疾患適応におけるThbsとERストレスとの潜在的な関連は未調査です.
研究 の 目的:
- 適応的なERストレス反応の効果因子としてのThrombospondins (Thbs) の役割を調査する.
- 心臓の損傷と適応不良におけるThbs4の機能を決定する.
- ThbsがER機能と細胞保護に影響を与えるメカニズムを解明する.
主な方法:
- 心臓特異的なThbs4トランスジェニックとThbs4ノックアウトマウスモデルを使用しました.
- 適応的なERストレス反応因子とER形態論を分析した.
- Thbsと活性化転写因子6α (Atf6α) の相互作用を vivoおよびin vitroで調査しました.
- 評価された心臓損傷と適応不良のフェノタイプ.
主要な成果:
- Thbs4トランスジェニックのマウスは心筋損傷から保護され,Thbs4(-/-) のマウスは感受性であった.
- Thbs誘導は,適応的なERストレス因子プロファイルとER拡張につながりました.
- ThbsはAtf6αのER光領域に結合し,その核転位を促進します.
- Thbs4(-/-) マウスは,鈍化したAtf6α活性化を示し,Thbs4媒介による保護はAtf6αに依存していた.
結論:
- Thrombospondins (Thbs) は,適応的なERストレス反応のER居住エフェクタとして細胞内機能します.
- Thbs4は,Atf6α調節によるER機能を増強することによって,心臓の改造に保護的役割を果たします.
- このメカニズムは,ERストレスを伴う心血管疾患の潜在的な治療目標としてThbsを強調しています.
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