DPP9によるNLRP1抑制の構造的および生化学的メカニズム
Menghang Huang1, Xiaoxiao Zhang1, Gee Ann Toh2
1Beijing Advanced Innovation Center for Structural Biology, Tsinghua-Peking Joint Center for Life Sciences, Center for Plant Biology, School of Life Sciences, Tsinghua University, Beijing, China.
Nature
|March 18, 2021
まとめ
ディペプチジルペプチダゼDPP8とDPP9はNLRP1炎症体の活性化を抑制する. 構造的および生化学的研究により,DPP9はNLRP1と複合体を形成し,自己抑制メカニズムを通じてその活性化を阻害する.
科学分野:
- 免疫学
- 分子生物学
- 構造生物学
背景:
- ヌクレオチド結合ドメイン,ルシン豊富なリピート受容体 (NLRs) は,炎症体形成による先天性免疫の重要な媒介体である.
- NLRP1炎症ゾームの活性化は,そのFunction-to-find領域 (FIIND) 内の自己分裂に依存する.
- ディペプチジルペプチダゼDPP8とDPP9はNLRP1の活性化を抑制することが知られているが,そのメカニズムは不明である.
研究 の 目的:
- DPP9がNLRP1の活性化を抑制するメカニズムを解明する.
- NLRP1とDPP9の相互作用の構造的根拠を調査する.
主な方法:
- NLRP1-DPP9複合体の構造を決定するX線結晶学.
- 結合と酵素活性を評価する生化学的測定法
- NLRP1阻害を評価するためのヒト細胞での機能検査
主要な成果:
- ラットNLRP1 (rNLRP1) とラットDPP9 (rDPP9) の2:1複合体は,自己抑制されたrNLRP1と活性UPA- CARD断片を含んでいる.
- NLRP1のZU5ドメインは,自己抑制と複合組成に不可欠です.
- DPP9結合と酵素活性の両方が,ヒト細胞におけるNLRP1活性化を抑制するために必要である.
結論:
- DPP9は,自己抑制を高める複合体を形成することによって,NLRP1炎症体の活性化を阻害する.
- この研究は,DPP9媒介によるNLRP1抑制の分子メカニズムを明らかにしています.
- 発見はNLRP1炎症体の活性化に関する洞察を提供します.
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