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Analysis of SCAP N-glycosylation and Trafficking in Human Cells
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スフィンゴシン-1-ホスファートは,E3ユビキチンリガゼTRAF2の欠けているコファクターです
Sergio E Alvarez1, Kuzhuvelil B Harikumar, Nitai C Hait
1Department of Biochemistry and Molecular Biology and the Massey Cancer Center, Virginia Commonwealth University School of Medicine, 1101 E. Marshall Street, Richmond, Virginia 23298, USA.
Nature
|June 26, 2010
まとめ
スフィンゴシン-1-ホスファート (S1P) は,TNF-αシグナル伝達における重要な酵素であるTRAF2のコファクターとして作用します. この発見は,炎症と免疫に不可欠なNF-kappaBの活性化を調節する新しいメカニズムを明らかにしています.
科学分野:
- 細胞の信号伝達経路は,
- 分子生物学は分子生物学である.
- バイオケミストリー バイオケミストリー
背景:
- 腫瘍死滅因子 (TNF) -αシグナリングは,免疫反応に不可欠な転写因子であるNF-kappaBを活性化します.
- TRAF2 (TNF受容体関連因子2) はNF-kappaBの活性化に不可欠ですが,RIP1のユビキチン化における直接的な役割は不明でした.
- スフィンゴシンキナーゼ1 (SphK1) は,細胞生存に関与する脂質媒介体であるスフィンゴシン-1-リン酸 (S1P) を生成します.
研究 の 目的:
- TRAF2媒介のNF-kappaB活性化におけるS1Pの役割を調査する.
- S1PがTRAF2のE3リガゼ活性にコファクターとして作用するかどうかを判断する.
- TRAF2媒介のRIP1ユビキチネーションのメカニズムを解明する.
主な方法:
- リコンビナントTRAF2およびRIP1.1を用いたインビトロユビキチネーションアッセイ.
- S1P生成の測定と,NF-kappaB経路のコンポーネントに対するその影響.
- S1PがTRAF2に結合する分析2.
主要な成果:
- SphK1と細胞内S1Pは,RIP1のユビキチン化,IKK/IkappaBalphaのリン酸化,NF-kappaBの活性化に不可欠である.
- S1Pは,TRAF2のRINGドメインに直接結合し,そのE3リガース活性を増強する.
- S1Pは特に,TRAF2.2によるRIP1のライシン-63関連ポリユビキチネーションを促進する.
結論:
- TRAF2は,S1P.の新たな細胞内標的である.
- S1Pは,TRAF2 E3ユビキチンリガース活性における重要なコファクターであり,ライシン-63結合型ポリユビキチン化を調節する.
- この発見は,SphK1/S1PとTRAF2.2によるNF-kappaB経路調節のための新しいパラダイムを確立しています.
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