Gasdermin E suppresses tumour growth by activating anti-tumour immunity

Zhibin Zhang (), Ying Zhang, Shiyu Xia, Qing Kong, Shunying Li, Xing Liu, Caroline Junqueira, Karla F. Meza-Sosa, Temy Mo Yin Mok, James Ansara, Satyaki Sengupta, Yandan Yao, Hao Wu and Judy Lieberman ()
Additional contact information
Zhibin Zhang: Boston Children’s Hospital
Ying Zhang: Boston Children’s Hospital
Shiyu Xia: Boston Children’s Hospital
Qing Kong: Dana-Farber Cancer Institute
Shunying Li: Sun Yat-Sen University
Xing Liu: Boston Children’s Hospital
Caroline Junqueira: Boston Children’s Hospital
Karla F. Meza-Sosa: Boston Children’s Hospital
Temy Mo Yin Mok: Boston Children’s Hospital
James Ansara: Boston Children’s Hospital
Satyaki Sengupta: Harvard Medical School
Yandan Yao: Sun Yat-Sen University
Hao Wu: Boston Children’s Hospital
Judy Lieberman: Boston Children’s Hospital

Nature, 2020, vol. 579, issue 7799, 415-420

Abstract: Abstract 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.

Date: 2020
References: Add references at CitEc
Citations: View citations in EconPapers (1)

Downloads: (external link)
https://www.nature.com/articles/s41586-020-2071-9 Abstract (text/html)
Access to the full text of the articles in this series is restricted.

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:nature:v:579:y:2020:i:7799:d:10.1038_s41586-020-2071-9

Ordering information: This journal article can be ordered from
https://www.nature.com/

DOI: 10.1038/s41586-020-2071-9

Access Statistics for this article

Nature is currently edited by Magdalena Skipper

More articles in Nature from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().