Granzyme A from cytotoxic lymphocytes cleaves GSDMB to trigger pyroptosis in target cells

被引：1021

作者：

Zhou, Zhiwei ^{[1
,2
]}

He, Huabin ^{[2
,3
]}

Wang, Kun ^{[2
]}

Shi, Xuyan ^{[2
]}

Wang, Yupeng ^{[1
,2
]}

Su, Ya ^{[2
]}

Wang, Yao ^{[4
,5
]}

Li, Da ^{[2
]}

Liu, Wang ^{[1
,2
]}

Zhang, Yongliang ^{[6
]}

Shen, Lianjun ^{[6
]}

Han, Weidong ^{[4
,5
]}

Shen, Lin ^{[7
]}

Ding, Jingjin ^{[2
,8
]}

Shao, Feng ^{[1
,2
,8
,9
]}

机构：

[1] Chinese Acad Med Sci, Res Unit Pyroptosis & Immun, Beijing 102206, Peoples R China

[2] Natl Inst Biol Sci, Beijing 102206, Peoples R China

[3] Tsinghua Univ, Peking Univ Tsinghua Univ Natl Inst Biol Sci Join, Sch Life Sci, Beijing 100084, Peoples R China

[4] Chinese Peoples Liberat Army Gen Hosp, Dept Mol & Immunol, Beijing 100853, Peoples R China

[5] Chinese Peoples Liberat Army Gen Hosp, Dept Biotherapeut, Beijing 100853, Peoples R China

[6] Gracell Biotechnol, Shanghai 200233, Peoples R China

[7] Peking Univ, Canc Hosp & Inst, Dept Gastrointestinal Oncol, Beijing 100142, Peoples R China

[8] Chinese Acad Sci, Inst Biophys, CAS Ctr Excellence Biomacromol, Natl Lab Biomacromol, Beijing 100101, Peoples R China

[9] Tsinghua Univ, Tsinghua Inst Multidisciplinary Biomed Res, Beijing 102206, Peoples R China

来源：

SCIENCE | 2020年 / 368卷 / 6494期

基金：

中国国家自然科学基金;

关键词：

NATURAL-KILLER-CELLS; T-CELLS; INFLAMMATORY CASPASES; MOUSE GRANZYME; MEDIATED LYSIS; GASDERMIN D; DFNA5; GENE; DEATH; APOPTOSIS; PERFORIN;

D O I：

10.1126/science.aaz7548

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Cytotoxic lymphocyte-mediated immunity relies on granzymes. Granzymes are thought to kill target cells by inducing apoptosis, although the underlying mechanisms are not fully understood. Here, we report that natural killer cells and cytotoxic T lymphocytes kill gasdermin B (GSDMB)-positive cells through pyroptosis, a form of proinflammatory cell death executed by the gasdermin family of poreforming proteins. Killing results from the cleavage of GSDMB by lymphocyte-derived granzyme A (GZMA), which unleashes its pore-forming activity. Interferon-g (IFN-g) up-regulates GSDMB expression and promotes pyroptosis. GSDMB is highly expressed in certain tissues, particularly digestive tract epithelia, including derived tumors. Introducing GZMA-cleavable GSDMB into mouse cancer cells promotes tumor clearance in mice. This study establishes gasdermin-mediated pyroptosis as a cytotoxic lymphocyte-killing mechanism, which may enhance antitumor immunity. © 2020 American Association for the Advancement of Science. All rights reserved.

引用

页码：965 / +

页数：42

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