Gasdermin E suppresses tumour growth by activating anti-tumour immunity

Research output: Journal Publications and Reviews (RGC: 21, 22, 62)21_Publication in refereed journalpeer-review

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Author(s)

  • Zhibin Zhang
  • Ying Zhang
  • Shiyu Xia
  • Qing Kong
  • Shunying Li
  • Xing Liu
  • Caroline Junqueira
  • Karla F. Meza-Sosa
  • James Ansara
  • Satyaki Sengupta
  • Yandan Yao
  • Hao Wu
  • Judy Lieberman

Related Research Unit(s)

Detail(s)

Original languageEnglish
Pages (from-to)415-420
Journal / PublicationNature
Volume579
Issue number7799
Online published11 Mar 2020
Publication statusPublished - 19 Mar 2020

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.

Citation Format(s)

Gasdermin E suppresses tumour growth by activating anti-tumour immunity. / Zhang, Zhibin; Zhang, Ying; Xia, Shiyu; Kong, Qing; Li, Shunying; Liu, Xing; Junqueira, Caroline; Meza-Sosa, Karla F.; Mok, Temy Mo Yin; Ansara, James; Sengupta, Satyaki; Yao, Yandan; Wu, Hao; Lieberman, Judy.

In: Nature, Vol. 579, No. 7799, 19.03.2020, p. 415-420.

Research output: Journal Publications and Reviews (RGC: 21, 22, 62)21_Publication in refereed journalpeer-review