炎症性カスパースによるGSDMDの割れは,炎症性細胞死亡を決定する

Jianjin Shi^1,2, Yue Zhao², Kun Wang²

¹Peking University-Tsinghua University-National Institute of Biological Sciences Joint Graduate Program, School of Life Sciences, Tsinghua University, 100084, China.

Nature

|September 17, 2015

まとめ

炎症性カスパスは,重要な免疫タンパク質であるガスダーミンD (GSDMD) を分裂させ,ピロプトーシスを活性化します. この割れはGSDMDを放出する.

科学分野:

免疫学
細胞生物学
分子機構

背景:

炎症性カスパース (カスパース-1, -4, -5, -11) は先天的な免疫に不可欠であり,熱死を引き起こす.
炎症性カスパスが熱死を引き起こす正確なメカニズムは,ほとんど知られていなかった.

研究の目的:

炎症性カスパスによる熱死誘発の分子メカニズムを解明する.
カスパース-11とカスパース-1誘発の炎症を媒介する主要な宿主因子を特定する.

主な方法:

マウスの骨髄マクロファージにおける全ゲノムCRISPR-Cas9スクリーニング
GSDMD欠乏細胞におけるピロプトーシス誘導とインタールイキン-1β放出の分析
ガスダーミン族のタンパク質の炎症性カスパース分裂部位を決定する生化学的測定

主要な成果:

ガスダーミンD (GSDMD) は,熱中症の重要な媒介体として特定されました.
GSDMD欠乏した細胞は,LPSと炎症性リガンドによって誘発された熱滅菌に耐性がある.
カスパース-1とカスパース-4/5/11は,特にGSDMDを割って,その熱滅菌誘発性N末端領域を放出する.
GSDMA3における機能獲得変異は,そのN末端ドメインの炎症誘発活性も明らかにした.

結論:

GSDMDは,炎症性カスパース媒介性熱死の直接的な原因です.
炎症性カスパースによるGSDMDの割れは,炎症性カスパースにとって不可欠であり,十分である.
これらの発見は,炎症体,カスパス,およびプログラムされた細胞死との間のメカニズム的なリンクを提供します.

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