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LUBACは細胞死を防止し,血液形成を可能にすることで,胚形成に不可欠です

Nieves Peltzer¹, Maurice Darding¹, Antonella Montinaro¹

¹UCL Cancer Institute, University College London, London, UK.

|April 27, 2018

まとめ

HOIL-1は,線形ユビキチンチェーンアセンブリ複合体 (LUBAC) の機能に不可欠であり,胚形成中に異常な細胞死を防ぐために適切なアセンブリと安定性を確保します. HOIL-1欠乏症は胚性死亡を引き起こし,LUBAC媒介のTNFR1シグナル伝達においてHOIPと共に重要な役割を果たしている.

科学分野:

分子生物学
免疫学
発達生物学

背景:

線形ユビキチンチェーンアセンブリ複合体 (LUBAC) は,免疫受容体,特にTNFR1のシグナル伝達に不可欠であり,遺伝子の活性化と細胞死に影響を与えます.
SHARPINやHOIPのようなLUBAC成分の欠乏は,マウスで重度の炎症や胚死亡を引き起こす.
HOIL-1欠乏症はヒトで炎症性疾患を引き起こすが,マウスにおけるその役割は以前は不明であった.

研究の目的:

LUBAC機能におけるHOIL-1の重要な役割とその胚形成への影響を調査する.
HOIL-1がLUBACの組み立て,安定性,TNFR1のシグナル伝達に寄与する特定のメカニズムを解明する.
胚の発達中のHOIL-1,HOIP,RIPK1,RIPK3,MLKL,およびカスパース-8を含む補償経路と遺伝的相互作用を理解する.

主な方法:

HOIL-1欠乏マウス (Hoil-1-/-またはRbck1-/-) の生成と分析
細胞死経路の重要な成分 (RIPK1,RIPK3,MLKL,カスパース-8) の共削除を含む遺伝子操作.
胚の死亡率,細胞死経路,およびノックアウトモデルにおける血液形成の評価.

主要な成果:

HOIL-1は,TNFR1複合体におけるLUBACの組み立て,安定性,および保持に不可欠であり,異常な細胞死を防止します.
HOIL-1とHOIPは,部分的にRIPK1に依存するTNFR1媒介の内皮細胞死を通して,妊娠中期の胚死亡を防ぐ.
HOIL-1欠乏症の生存可能なマウスは,カスパース-8とMLKLの結合削除を必要とします.しかし,トリプルノックアウト (Ripk3-/-Casp8-/-Hoil-1-/-) は,RIPK1の削除によって救出された血液形成の欠陥のために妊娠後期に死亡します.

結論:

HOIL-1は,HOIPと同様に,異常な細胞死を防ぐことで,LUBACの機能と胚形成に不可欠です.
RIPK3は,LUBACとカスパース-8が欠けているとき,血液形成の欠陥によるRIPK1誘発の胚死亡を防止する重要な調節剤として作用する.

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