Gasdermin E suppresses tumor growth by activating anti-tumor immunity

By Zhibin Zhang, Ying Zhang, S. Xia, Qing Kong, Shunying Li, Xing Liu, Caroline Junqueira, Karla F. Meza-Sosa, Mo Yin Temy Mok, James A Ansara and 4 more. Nature, 2020

1,396 citations recorded by the source corpus.

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.

Subfields: Cell Biology, Molecular Biology, Molecular Medicine

View Paper: https://www.semanticscholar.org/paper/6409eead6cf56822c044ff1cb21801a77e90caea

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Citations in the corpus

Pyroptosis in inflammatory diseases and cancer (2022, background): “Natural killer cell-derived granzyme B (GZMB) can directly cleave GSDME at the same site that is cleaved by caspase-3, leading to the release of the effector N-terminal, which perforates the cell membrane [51].”
Pyroptosis: mechanisms and diseases (2021, background): “In 2020, it was reported that granzyme B (GzmB) can directly cleave GSDME and activate pyroptosis, further activating the antitumor immune response and inhibiting tumor growth.(19) In the same year, granzyme A (GzmA) in cytotoxic lymphocytes was found to enter target cells through perforin and induc”