リン酸化と直線的なユビキチンA20の炎症抑制

Ingrid E Wertz^1,2, Kim Newton³, Dhaya Seshasayee⁴

¹Discovery Oncology, Genentech, South San Francisco, California 94080, USA.

Nature

|December 10, 2015

まとめ

A20タンパク質 (TNFAIP3遺伝子) は炎症と細胞死を調節する. リウマチ性関節炎のような炎症性疾患に影響を与える.

科学分野:

分子生物学
免疫学
遺伝学

背景:

A20タンパク質をコードするTNFAIP3遺伝子は,炎症性疾患に関連しています.
炎症信号を弱めるA20の役割は,in vitroとin vivoのデータが矛盾しているため,矛盾しています.

研究の目的:

遺伝子組み換えマウスモデルを使って A20機能の不一致を調査する.
炎症と細胞死を調節するA20の分子メカニズムを解明する.

主な方法:

A20のOTUデウビキチナーゼ領域とZnF4ユビキチン結合モチーフの変異を有する遺伝子組み換えマウスを利用した.
炎症シグナル伝達経路に対するA20酸化とユビキチネーションの影響を分析した.

主要な成果:

A20のリン酸化はデウビキチナゼの活性と基質のユビキチネーションを高めます.
線形ユビキチネーションレベルは,腫瘍死因 (TNF) に反応する細胞死を決定する.
線形ユビキチン鎖はTNFR1複合体を安定させ,A20媒介のエスカフォードの分解を防ぐ.

結論:

A20デウビキチン酵素の活性,ユビキチン結合,線形ユビキチン化,およびキナーゼは,炎症と細胞死を制御するために協力する.
これらの発見は,炎症シグナル伝達におけるA20の機能の分子基盤を明らかにする.

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