cGASのDNA誘発液相凝縮は,先天的な免疫信号を活性化する

Mingjian Du^1,2, Zhijian J Chen^3,2,4

¹Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9148, USA.

Science (New York, N.Y.)

|July 7, 2018

まとめ

サイクルGMP- AMP合成酵素 (cGAS) はDNA結合時に液滴を形成し,先天的な免疫信号を強める. 亜鉛イオンと長いDNAは,この相分離を促進することによって,cGAS活動をさらに強化します.

科学分野:

生物化学
免疫学
分子生物学

背景:

循環型GMP- AMP合成酵素 (cGAS) は,先天的な免疫反応を誘発する細胞塩基DNAの重要なセンサーである.
cGASによって生成されるcGAMPは,抗ウイルスおよび抗菌免疫に不可欠なSTING経路を活性化します.

研究の目的:

cGAS活性化におけるDNA結合誘発相分離の役割を調査する.
DNA特性と亜鉛イオンがcGAS活性と相分離にどのように影響するか調べる.

主な方法:

cGASとDNAを用いた in vitro 段階分離試験
cGAMPの生成を測定する酵素活性測定法
亜鉛の存在下でのcGAS活性を評価するための細胞ベースの実験.

主要な成果:

cGASへのDNA結合は,活性化されたcGASを濃縮した液体のような滴の形成を強固に誘導しました.
乱れた,陽性電荷のcGAS N端は,DNA結合バレンスを増加させ,相分離を促進した.
cGASの液相分離と酵素活性を促進するために,より長いDNA分子はより短かった.
自由亜鉛イオンは,cGAS酵素の活性を増強し,cGASとDNAの相分離をインビトロと細胞で促進した.

結論:

cGASのDNA誘発の相変異は,cGAMPの生成を促進する重要なメカニズムである.
段階分離は,cGASを濃縮して活性化することによって,先天的な免疫シグナル伝達を強化します.
亜鉛イオンは,cGAS媒介の先天性免疫の潜在的調節剤である.

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