2. Academic Validation
  3. Granzyme A from cytotoxic lymphocytes cleaves GSDMB to trigger pyroptosis in target cells

Granzyme A from cytotoxic lymphocytes cleaves GSDMB to trigger pyroptosis in target cells

  • Science. 2020 May 29;368(6494):eaaz7548. doi: 10.1126/science.aaz7548.
Zhiwei Zhou # 1 2,  Huabin He # 3 2,  Kun Wang 2,  Xuyan Shi 2,  Yupeng Wang 1 2,  Ya Su 2,  Yao Wang 4,  Da Li 2,  Wang Liu 1 2,  Yongliang Zhang 5,  Lianjun Shen 5,  Weidong Han 4,  Lin Shen 6,  Jingjin Ding 2 7,  Feng Shao 8 2 7 9
Affiliations

Affiliations

  • 1 Research Unit of Pyroptosis and Immunity, Chinese Academy of Medical Sciences and National Institute of Biological Sciences, Beijing, Beijing 102206, China.
  • 2 National Institute of Biological Sciences, Beijing, Beijing 102206, China.
  • 3 Peking University-Tsinghua University-National Institute of Biological Sciences Joint Graduate Program, School of Life Sciences, Tsinghua University, Beijing 100084, China.
  • 4 Department of Molecular and Immunology and Department of Bio-therapeutics, Chinese PLA General Hospital, Beijing 100853, China.
  • 5 Gracell Biotechnologies, Shanghai 200233, China.
  • 6 Department of Gastrointestinal Oncology, Peking University Cancer Hospital and Institute, Beijing 100142, China.
  • 7 National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences (CAS), Beijing 100101, China.
  • 8 Research Unit of Pyroptosis and Immunity, Chinese Academy of Medical Sciences and National Institute of Biological Sciences, Beijing, Beijing 102206, China. shaofeng@nibs.ac.cn.
  • 9 Tsinghua Institute of Multidisciplinary Biomedical Research, Tsinghua University, Beijing 102206, China.
  • # Contributed equally.
PMID: 32299851 DOI: 10.1126/science.aaz7548
Abstract

Cytotoxic lymphocyte-mediated immunity relies on granzymes. Granzymes are thought to kill target cells by inducing Apoptosis, although the underlying mechanisms are not fully understood. Here, we report that natural killer cells and cytotoxic T lymphocytes kill gasdermin B (GSDMB)-positive cells through Pyroptosis, a form of proinflammatory cell death executed by the gasdermin family of pore-forming proteins. Killing results from the cleavage of GSDMB by lymphocyte-derived granzyme A (GZMA), which unleashes its pore-forming activity. Interferon-γ (IFN-γ) up-regulates GSDMB expression and promotes Pyroptosis. GSDMB is highly expressed in certain tissues, particularly digestive tract epithelia, including derived tumors. Introducing GZMA-cleavable GSDMB into mouse Cancer cells promotes tumor clearance in mice. This study establishes gasdermin-mediated Pyroptosis as a cytotoxic lymphocyte-killing mechanism, which may enhance antitumor immunity.

Figures