| Author | Zhang, Zhibin | |
| Author | Zhang, Ying | |
| Author | Xia, Shiyu | |
| Author | Kong, Qing | |
| Author | Li, Shunying | |
| Author | Liu, Xing | |
| Author | Junqueira, Caroline | |
| Author | Meza-Sosa, Karla F | |
| Author | Mok, Temy Mo Yin | |
| Author | Ansara, James | |
| Author | Sengupta, Satyaki | |
| Author | Yao, Yandan | |
| Author | Wu, Hao | |
| Author | Lieberman, Judy | |
| Access date | 2023-05-17T12:07:39Z | |
| Available date | 2023-05-17T12:07:39Z | |
| Document date | 2020 | |
| Citation | ZHANG, Zhibin et al. Gasdermin E suppresses tumour growth by activating anti-tumour immunity. Nature, v. 579, n. 7799, p. 415-420, 2020. doi: 10.1038/s41586-020-2071-9. | en_US |
| ISSN | 0028-0836 | en_US |
| URI | https://www.arca.fiocruz.br/handle/icict/58452 | |
| Language | eng | en_US |
| Publisher | Nature Publishing Group | en_US |
| Rights | restricted access | |
| Title | Gasdermin E suppresses tumour growth by activating anti-tumour immunity | en_US |
| Type | Article | |
| DOI | 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 loss(2)-can be cleaved by caspase 3, thereby converting noninflammatory apoptosis to pyroptosis in GSDME-expressing cells(3-5). GSDME expression is suppressed in many cancers, and reduced GSDME levels are associated with decreased survival as a result of breast cancer(2,6), 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. | en_US |
| Affilliation | Program in Cellular and Molecular Medicine. Boston Children's Hospital. Boston, MA, USA/Department of Pediatrics. Harvard Medical School. Boston, MA, USA. | en_US |
| Affilliation | Program in Cellular and Molecular Medicine. Boston Children's Hospital, Boston. MA, USA/Department of Pediatrics. Harvard Medical School. Boston, MA, USA. | en_US |
| Affilliation | Program in Cellular and Molecular Medicine. Boston Children's Hospital, Boston. MA, USA/Department of Biological Chemistry and Molecular Pharmacology. Harvard Medical School. Boston, MA, USA. | en_US |
| Affilliation | Department of Cancer Biology. Dana-Farber Cancer Institute. Boston, MA, USA/Department of Genetics. Harvard Medical School. Boston, MA, USA. | en_US |
| Affilliation | Breast Tumor Center. Sun Yat-Sen Memorial Hospital. Sun Yat-Sen University. Guangzhou, China. | en_US |
| Affilliation | Program in Cellular and Molecular Medicine. Boston Children's Hospital, Boston. MA, USA/Department of Pediatrics. Harvard Medical School. Boston, MA, USA/The Center for Microbes. Development and Health. Key Laboratory of Molecular Virology and Immunology. Institut Pasteur of Shanghai. Chinese Academy of Sciences. Shanghai, China. | en_US |
| Affilliation | Program in Cellular and Molecular Medicine. Boston Children's Hospital, Boston. MA, USA/Department of Pediatrics. Harvard Medical School. Boston, MA, USA/ René Rachou Institute. Oswaldo Cruz Foundation. Belo Horizonte, MG, Brazil. | en_US |
| Affilliation | Program in Cellular and Molecular Medicine. Boston Children's Hospital, Boston. MA, USA/Department of Pediatrics. Harvard Medical School. Boston, MA, USA/Laboratorio de Neuroimmunobiología. Departamento de Medicina Molecular y Bioprocesos. Instituto de Biotecnología. Universidad Nacional Autónoma de México. Cuernavaca, Mexico. | en_US |
| Affilliation | Program in Cellular and Molecular Medicine. Boston Children's Hospital, Boston. MA, USA/Department of Pediatrics. Harvard Medical School. Boston, MA, USA/ Department of Biomedical Sciences. City University of Hong Kong. Hong Kong, Hong Kong. | en_US |
| Affilliation | Program in Cellular and Molecular Medicine. Boston Children's Hospital, Boston. MA, USA/Department of Pediatrics. Harvard Medical School. Boston, MA, USA | en_US |
| Affilliation | Department of Pediatrics. Harvard Medical School. Boston, MA, USA/Department of Pediatric Oncology. Dana-Farber Cancer Institute. Boston, MA, USA. | en_US |
| Affilliation | Breast Tumor Center. Sun Yat-Sen Memorial Hospital. Sun Yat-Sen University. Guangzhou, China. | en_US |
| Affilliation | Program in Cellular and Molecular Medicine. Boston Children's Hospital, Boston. MA, USA/Department of Biological Chemistry and Molecular Pharmacology. Harvard Medical School. Boston, MA, USA. | en_US |
| Affilliation | Program in Cellular and Molecular Medicine. Boston Children's Hospital. Boston, MA, USA/Department of Pediatrics. Harvard Medical School. Boston, MA, USA. | en_US |
