Gasdermin E suppresses tumour growth by activating anti-tumour immunity
Top Cited Papers
- 11 March 2020
- journal article
- research article
- Published by Springer Science and Business Media LLC in Nature
- Vol. 579 (7799), 415-420
- https://doi.org/10.1038/s41586-020-2071-9
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 cells3,4,5. 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.Keywords
This publication has 24 references indexed in Scilit:
- Vaccination with Necroptotic Cancer Cells Induces Efficient Anti-tumor ImmunityCell Reports, 2016
- A Small Molecule that Induces Intrinsic Pathway Apoptosis with Unparalleled SpeedCell Reports, 2015
- A High Yield and Cost-efficient Expression System of Human Granzymes in Mammalian CellsJournal of Visualized Experiments, 2015
- Improved vectors and genome-wide libraries for CRISPR screeningNature Methods, 2014
- Genome-Scale CRISPR-Cas9 Knockout Screening in Human CellsScience, 2014
- A Genome-wide siRNA Screen Identifies Proteasome Addiction as a Vulnerability of Basal-like Triple-Negative Breast Cancer CellsCancer Cell, 2013
- DFNA5, a Gene Involved in Hearing Loss and Cancer: A ReviewAnnals of Otology, Rhinology & Laryngology, 2012
- Isolation of Cytotoxic T Cell and NK Granules and Purification of Their Effector ProteinsCurrent Protocols in Cell Biology, 2010
- Death by a Thousand Cuts: Granzyme Pathways of Programmed Cell DeathAnnual Review of Immunology, 2008
- Structure–activity relationship study of novel necroptosis inhibitorsBioorganic & Medicinal Chemistry Letters, 2005