パルムデルフィンは,内皮内の機械的ストレスに対する核抵抗性を調節する

Miguel Sáinz-Jaspeado¹, Ross O Smith¹, Oscar Plunde²

¹Rudbeck, Beijer and SciLifeLab Laboratories, Department of Immunology, Genetics and Pathology (M.S.-J., R.O.S., Y.J., S.N., Y.D., P.A., M.H., L.C.-W.), Uppsala University, Sweden.

Circulation

|October 12, 2021

まとめ

パルムデルフィン (PALMD) 発現の低下は,大動脈弁の縮症と関連している. PALMDの喪失は内皮細胞の核輸送と細胞骨格の整合性を妨害し,疾患の病理に寄与する.

科学分野:

細胞生物学
分子生物学
心血管研究

背景:

パルムデルフィン (PALMD) は,細胞骨格の調節に関与するパラレミンタンパク質である.
シングルヌクレオチドポリモルフィズムによるPALMD発現の低下は,カルシフ性大動脈弁狭窄症 (CAVS) の危険因子である.

研究の目的:

PALMDとCAVSを結びつける分子メカニズムを調査する.
PALMDの細胞機能と内皮細胞 (EC) の相互作用パートナーを特定する.

主な方法:

PALMD発現を決定する免疫検知とデータベーススクリーニング.
マススペクトロメトリー,共免疫プレシピテーション,およびPALMDパートナーを特定するための免疫光.
siRNAで処理されたEC,ノックアウトマウス,および人間のサンプルで,PALMDの喪失の結果を評価する.
遺伝子制御分析のためのRNA配列とトランスクリプト配列.

主要な成果:

PALMDは,EC内のRANGAP1 (RAN GTPase活性化タンパク質1) と結合し,XPO1 (エクスポートイン1) 経由で核細胞質輸送に影響を与えます.
PALMD発現の減少は,RANGAP1/XPO1の転位,p53/p21の核停止,および機械的ストレスに対するEC反応の低下 (アクチンキャップの喪失) を引き起こします.
PALMD欠乏した細胞,組織,およびヒトCAVSのサンプルで核不整合および細胞骨格の欠陥が観察されました.

結論:

PALMD/RANGAP1複合体は,ECの核細胞伝達と核弾性維持に不可欠である.
この複合体の破壊は遺伝子調節の変化と細胞骨格の異常を引き起こす.
これらの発見は,PALMDの発現の減少と,カルシフ性大動脈弁の狭窄の病原性との間にメカニズム的な関連性を示しています.

キーワード:

大動脈弁の狭窄内皮細胞核サイトプラズマ輸送パーム・デルフィーン

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