OTULINは,LUBACをデビキチン化することで,細胞死と炎症を抑制する

Klaus Heger¹, Katherine E Wickliffe¹, Ada Ndoja¹

¹Department of Physiological Chemistry, Genentech, South San Francisco, CA, USA.

Nature

|June 29, 2018

まとめ

OTULINタンパク質は,炎症と胚死亡を防ぐために重要な複合体であるLUBACの自己ユビキチン化を防ぐ. OTULINの機能の喪失は細胞死とI型インターフェロンの生成につながります.

科学分野:

細胞生物学
免疫学
分子生物学

背景:

OTULIN (線形結合特異性を持つOTUデウビキチン酵素) は,線形ポリユビキチンをLUBAC (線形ユビキチン鎖組立複合体) 基板から除去する.
OTULINは,自己炎症性疾患と胎児死亡の予防に不可欠です.

研究の目的:

LUBACの活性とその下流の影響を正確に調査する.
OTULINの欠乏が胚死亡と自己炎症につながるメカニズムを解明する.

主な方法:

触媒的に不活性なOTULINを発現するノックインマウスの生成
OTULIN欠乏モデルにおける細胞死経路 (TNFR1,RIPK1,カスパース8,RIPK3) の分析
変異したマウスのタイプIインターフェロン生成の評価

主要な成果:

TNFR1/ RIPK1媒介の細胞死による妊娠中期の胚死亡を引き起こします.
成人マウスのOTULINの不活性化により,炎症性細胞死が引き起こされ,カスパース8とRIPK3の結合喪失によって回復します.
カスパース8とRIPK3を欠いたOTULIN変異マウスは,RIPK1依存型I型インターフェロンの産生を強めた末期死亡率を示した.

結論:

OTULINとLUBACは線形経路で機能し,OTULINは LUBACのオートユビキチン化を防止することによってその活動を促進する.
OTULINは細胞死経路とI型インターフェロン誘導の調節に重要な役割を果たします.
これらの発見は,線形的なユビキチン化,細胞死,先天的な免疫反応の間の新しいリンクを明らかにしています.

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