TY - JOUR
T1 - Gasdermin E suppresses tumour growth by activating anti-tumour immunity
AU - Zhang, Zhibin
AU - Zhang, Ying
AU - Xia, Shiyu
AU - Kong, Qing
AU - Li, Shunying
AU - Liu, Xing
AU - Junqueira, Caroline
AU - Meza-Sosa, Karla F.
AU - Mok, Temy Mo Yin
AU - Ansara, James
AU - Sengupta, Satyaki
AU - Yao, Yandan
AU - Wu, Hao
AU - Lieberman, Judy
N1 - Funding Information:
Acknowledgements We thank the US National Institutes of Health (NIH) Tetramer Core Facility for providing the eGFP tetramer. This work was supported by NIH grant R01 AI139914 (to H.W. and J.L.), a Charles A. King Trust Fellowship (to Z.Z.) and a Department of Defense Breast Cancer Breakthrough Fellowship Award (to Y.Z.). The mutations in GSDME primary tumours and primary human breast cancer and colorectal cancer expression analyses in this study are based upon data generated by The Cancer Genome Atlas (TCGA) Research Network (https:// www.cancer.gov/tcga).
Publisher Copyright:
© 2020, The Author(s), under exclusive licence to Springer Nature Limited.
PY - 2020/3/19
Y1 - 2020/3/19
N2 - 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.
AB - 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.
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U2 - 10.1038/s41586-020-2071-9
DO - 10.1038/s41586-020-2071-9
M3 - Article
C2 - 32188940
AN - SCOPUS:85081920360
SN - 0028-0836
VL - 579
SP - 415
EP - 420
JO - Nature
JF - Nature
IS - 7799
ER -