上睑下垂
颗粒酶B
细胞毒性T细胞
癌症研究
细胞凋亡
CD8型
异位表达
生物
程序性细胞死亡
抑制器
免疫学
免疫系统
化学
癌症
细胞培养
生物化学
体外
遗传学
作者
Zhibin Zhang,Ying Zhang,Shiyu Xia,Qing Kong,Shunying Li,Xing Liu,Caroline Junqueira,Karla F. Meza-Sosa,Temy Mok,James Ansara,Satyaki Sengupta,Yihong Yao,Hao Wu,Judy Lieberman
出处
期刊:Nature
[Springer Nature]
日期:2020-03-11
卷期号:579 (7799): 415-420
被引量:938
标识
DOI:10.1038/s41586-020-2071-9
摘要
Cleavage of the gasdermin proteins to produce pore-forming amino-terminal fragments causes inflammatory cell death (pyroptosis)1. Gasdermin E (GSDME, also known as DFNA5)—mutated in familial ageing-related hearing loss2—can be cleaved by caspase 3, thereby converting noninflammatory apoptosis to pyroptosis in GSDME-expressing cells3–5. GSDME expression is suppressed in many cancers, and reduced GSDME levels are associated with decreased survival as a result of breast cancer2,6, suggesting that GSDME might be a tumour suppressor. Here we show that 20 of 22 tested cancer-associated GSDME mutations reduce GSDME function. In mice, knocking out Gsdme in GSDME-expressing tumours enhances, whereas ectopic expression in Gsdme-repressed tumours inhibits, tumour growth. This tumour suppression is mediated by killer cytotoxic lymphocytes: it is abrogated in perforin-deficient mice or mice depleted of killer lymphocytes. GSDME expression enhances the phagocytosis of tumour cells by tumour-associated macrophages, as well as the number and functions of tumour-infiltrating natural-killer and CD8+ T lymphocytes. Killer-cell granzyme B also activates caspase-independent pyroptosis in target cells by directly cleaving GSDME at the same site as caspase 3. Uncleavable or pore-defective GSDME proteins are not tumour suppressive. Thus, tumour GSDME acts as a tumour suppressor by activating pyroptosis, enhancing anti-tumour immunity. The gasdermin E protein is shown to act as a tumour suppressor: it is cleaved by caspase 3 and granzyme B and leads to pyroptosis of cancer cells, provoking an immune response to the tumour.
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