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E3 ウビキチンリガゼWWP1をターゲットにすることで,K27関連ウビキチネーションを阻害することによって,DVL2を不安定化させ,心筋縮を防ぐ

Dingsheng Zhao¹, Guohui Zhong^1,2, Jianwei Li¹

¹State Key Laboratory of Space Medicine Fundamentals and Application, China Astronaut Research and Training Center, Beijing (D.Z., G.Z., J.L., W.S., X.J., Yuheng Li, R.D., J.N., X.Y., Zizhong Liu, J.S., G.K., Youyou Li, C.L., X.G., W.X., Yingxian Li, S.L.).

|June 18, 2021

まとめ

WWP1 (WWドメインを含むE3ユビキチンタンパク質リガゼ1) は,DVL2を安定させ,心臓機能不全の潜在的治療標的となるため,心筋縮を悪化させる. WWP1をターゲットにすると,圧力の過負荷による心臓機能不全を防ぐことができます.

科学分野:

心血管生物学
分子心臓科
生物化学

背景:

心圧過負荷による病理性心筋縮は心不全を引き起こします
WWP1 (WWドメインを含むE3ユビキチンタンパク質リガゼ1) は,老化に関連する疾患に関与しているが,心臓の改造におけるその役割は不明である.

研究の目的:

圧力過負荷による心筋縮と心不全におけるWWP1の役割を調査する.
WWP1が心臓の改造を制御する分子メカニズムを解明する.

主な方法:

心不全患者および横動脈収縮 (TAC) を受けたマウスのWWP1発現を分析した.
心臓機能と分子マーカーをWWP1ノックアウトマウスで評価した.
WWP1と相互作用するタンパク質を特定し,DVL2のWWP1によるユビキチネーションを調査した.
DVL2/CaMKII/HDAC4/MEF2C経路とWWP1を標的とした治療の可能性を調査した.

主要な成果:

濃度が高くなっていた.
"WWP"のノックアウトは TACによって引き起こされる心筋縮を防ぎます
WWP1は,K27結合ポリユビキチン化によってDVL2と直接相互作用し,安定させました.
WWP1をターゲットにすることで,TACによる心臓機能不全が改善されました.

結論:

WWP1は重圧による心臓改造の重要な治療標的である.
WWP1は,DVL2のK27関連ポリユビキチン化経由でDVL2/CaMKII/HDAC4/MEF2C経路を通じた心筋高縮を悪化させる.

キーワード:

DVL2 について WWP1 について心臓病についてハイパートロフィー非正規の Wnt ユビキチネーション

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