RIPK1は,発達中のZBP1誘発性死滅を抑制する
Kim Newton1, Katherine E Wickliffe1, Allie Maltzman1
1Department of Physiological Chemistry, Genentech, 1 DNA Way, South San Francisco, California 94080, USA.
Nature
|November 8, 2016
まとめ
受容体相互作用タンパク質キナーゼ1 (RIPK1) は通常,Z- DNA結合タンパク質1 (ZBP1) がRIPK3- 依存性死滅を引き起こすのを防ぐ. RIPK1の損失
科学分野:
- 細胞生物学
- 免疫学
- 細胞死亡の分子機構
背景:
- RIPK1の欠乏は,異常なアポトーシスとネクロプトーシスによる胎児死亡につながるため,受容体相互作用タンパク質キナーゼ1 (RIPK1) は細胞生存に不可欠です.
- 触媒的に不活性なRIPK1変異体は生存を可能にし,骨組みの機能を示唆しますが,細胞死経路の調節におけるRIPK1の正確な役割は,まだ完全に理解されていません.
- RIP同型相互作用モチーフ (RHIM) は,細胞死シグナル内のタンパク質-タンパク質相互作用に関与するRIPK1の重要な領域である.
研究 の 目的:
- 発達の過程でプログラムされた細胞死亡を防ぐために,受容体相互作用タンパク質キナーゼ1 (RIPK1) のRIP同型相互作用モチーフ (RHIM) の役割を調査する.
- RIPK1,Z-DNA結合タンパク質1 (ZBP1) とRIPK3との相互作用を解明する.
- ZBP1によるRIPK3の活性化が,RIPK1機能障害のマウスで観察された致死率に寄与するかどうかを判断する.
主な方法:
- Ripk1RHIM/RHIMが変異したマウスのRIPK1RHIM残留物の生成と分析
- ネクロプトーシスマーカー (RIPK3自己リン酸化) と遺伝子組み換えマウスモデルでの致死率の評価 (例えば,Ripk3ノックアウト,MLKLノックアウト).
- 様々な遺伝的背景におけるZBP1とRIPK3のタンパク質相互作用を研究する共免疫降水測定法.
主要な成果:
- 変異したRHIM (Ripk1RHIM/ RHIM) を有するRIPK1を発現したマウスは,生後死亡率とRIPK3自酸化を示した.
- RIPK3またはMLKLの遺伝的欠乏によって,または触媒的に不活性なRIPK3を使用することによって,Ripk1RHIM/RHIMマウスの死亡率を救出しました.
- Z- DNA結合タンパク質1 (ZBP1) の喪失は,Ripk1RHIM/ RHIMのマウスにおける致死性を防止し,ZBP1は機能するRIPK1とMLKLの欠如においてRIPK3と相互作用した.
結論:
- RIPK1のRHIMドメインは,ZBP1がRIPK3を不適切に誘導し,発達中に死滅を引き起こすのを防ぐ重要なブレーキとして作用します.
- ZBP1- RIPK3- MLKL依存性死滅は,正常な胚および胎内生存のためにRIPK1によって抑制されなければならない重要な経路である.
- これらの発見は,ZBP1媒介性ネクロプトシス信号を制御することによって,RIPK1 RHIMの新たな抑制作用を明らかにしています.
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