Open AccessGasdermin E suppresses tumour growth by activating anti-tumour immunity
Author(s) -
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
Publication year - 2020
Publication title -
nature
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 15.993
H-Index - 1226
eISSN - 1476-4687
pISSN - 0028-0836
DOI - 10.1038/s41586-020-2071-9
Subject(s) - pyroptosis , granzyme b , cytotoxic t cell , cancer research , apoptosis , cd8 , immune system , ectopic expression , biology , programmed cell death , suppressor , chemistry , immunology , cancer , cell culture , biochemistry , in vitro , genetics
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 loss 2 -can be cleaved by caspase 3, thereby converting noninflammatory apoptosis to pyroptosis in GSDME-expressing cells 3-5 . GSDME expression is suppressed in many cancers, and reduced GSDME levels are associated with decreased survival as a result of breast cancer 2,6 , 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.