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https://www.arca.fiocruz.br/handle/icict/58452
GASDERMIN E SUPPRESSES TUMOUR GROWTH BY ACTIVATING ANTI-TUMOUR IMMUNITY
Author
Affilliation
Program in Cellular and Molecular Medicine. Boston Children's Hospital. Boston, MA, USA/Department of Pediatrics. Harvard Medical School. Boston, MA, USA.
Program in Cellular and Molecular Medicine. Boston Children's Hospital, Boston. MA, USA/Department of Pediatrics. Harvard Medical School. Boston, MA, USA.
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.
Department of Cancer Biology. Dana-Farber Cancer Institute. Boston, MA, USA/Department of Genetics. Harvard Medical School. Boston, MA, USA.
Breast Tumor Center. Sun Yat-Sen Memorial Hospital. Sun Yat-Sen University. Guangzhou, China.
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.
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.
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.
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.
Program in Cellular and Molecular Medicine. Boston Children's Hospital, Boston. MA, USA/Department of Pediatrics. Harvard Medical School. Boston, MA, USA
Department of Pediatrics. Harvard Medical School. Boston, MA, USA/Department of Pediatric Oncology. Dana-Farber Cancer Institute. Boston, MA, USA.
Breast Tumor Center. Sun Yat-Sen Memorial Hospital. Sun Yat-Sen University. Guangzhou, China.
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.
Program in Cellular and Molecular Medicine. Boston Children's Hospital. Boston, MA, USA/Department of Pediatrics. Harvard Medical School. Boston, MA, USA.
Program in Cellular and Molecular Medicine. Boston Children's Hospital, Boston. MA, USA/Department of Pediatrics. Harvard Medical School. Boston, MA, USA.
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.
Department of Cancer Biology. Dana-Farber Cancer Institute. Boston, MA, USA/Department of Genetics. Harvard Medical School. Boston, MA, USA.
Breast Tumor Center. Sun Yat-Sen Memorial Hospital. Sun Yat-Sen University. Guangzhou, China.
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.
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.
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.
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.
Program in Cellular and Molecular Medicine. Boston Children's Hospital, Boston. MA, USA/Department of Pediatrics. Harvard Medical School. Boston, MA, USA
Department of Pediatrics. Harvard Medical School. Boston, MA, USA/Department of Pediatric Oncology. Dana-Farber Cancer Institute. Boston, MA, USA.
Breast Tumor Center. Sun Yat-Sen Memorial Hospital. Sun Yat-Sen University. Guangzhou, China.
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.
Program in Cellular and Molecular Medicine. Boston Children's Hospital. Boston, MA, USA/Department of Pediatrics. Harvard Medical School. Boston, MA, USA.
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.
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