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LZTR1の変異は,RASのユビキチン化を乱すことでヒトの病気を誘発する

M Steklov^1,2, S Pandolfi^1,2, M F Baietti^1,2

¹VIB-KU Leuven Center for Cancer Biology, VIB, 3000 Leuven, Belgium.

Science (New York, N.Y.)

|November 17, 2018

まとめ

レウシンジッパー型転写レギュレータ1 (LZTR1) タンパク質は,ユビキチネーションを媒介することによってRASシグナリングを調節する. LZTR1の機能の喪失はヌーナン症候群を引き起こし,シュヴァン細胞増殖に影響を与え,ヒトの病気におけるその役割を説明する.

科学分野:

分子生物学
遺伝学
細胞生物学

背景:

レウシンジッパー型転写レギュレータ1 (LZTR1) タンパク質は,カルリン3 (CUL3) ユビキチンリガゼ複合体のアダプタです.
LZTR1の正確な作用機構とヒトの疾患における役割は,ほとんど不明である.

研究の目的:

LZTR1機能の分子メカニズムを解明する.
LZTR1,RASシグナル伝達とヌーナン症候群のような人間の病気の関連を調べるため

主な方法:

哺乳類の細胞から LZTR1複合体を捕まえる
タンパク質のユビキチン化変化を特定するためのユビキトーム分析
病気に関連したLZTR1変異の分析

主要な成果:

LZTR1はCUL3ユビキチンリガゼ複合体のアダプタとして作用し,グアノシントリホスファタゼRASを標的とする.
LZTR1媒介によるRASのユビキチン化は,膜結合を減少させることでRASシグナル伝達を阻害する.
マウスにおけるLztr1の喪失は,ヌーナン症候群の表型を再現し,シュヴァン細胞の行動に影響する.
特定された疾患関連LZTR1変異は複合体形成またはRAS相互作用を阻害する.

結論:

LZTR1媒介によるRASのユビキチネーションは重要な規制メカニズムである.
この経路の調節不良は,ヌーナン症候群を含むヒトの疾患におけるLZTR1の関与を説明する.

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