1. Academic Validation
  2. Streptococcal pyrogenic exotoxin B cleaves GSDMA and triggers pyroptosis

Streptococcal pyrogenic exotoxin B cleaves GSDMA and triggers pyroptosis

  • Nature. 2022 Feb;602(7897):496-502. doi: 10.1038/s41586-021-04384-4.
Wanyan Deng # 1 2 3 Yang Bai # 1 4 Fan Deng # 1 4 Youdong Pan # 5 6 Shenglin Mei 7 Zengzhang Zheng 1 2 3 Rui Min 1 4 Zeyu Wu 1 4 Wu Li 1 2 3 Rui Miao 8 9 Zhibin Zhang 8 9 Thomas S Kupper 5 6 Judy Lieberman 8 9 Xing Liu 10 11 12
Affiliations

Affiliations

  • 1 The Center for Microbes, Development and Health, Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, China.
  • 2 The Joint Center for Infection and Immunity, Guangzhou Institute of Pediatrics, Guangzhou Women and Children's Medical Center, Guangzhou, China.
  • 3 The Joint Center for Infection and Immunity, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, China.
  • 4 University of Chinese Academy of Sciences, Beijing, China.
  • 5 Department of Dermatology, Brigham and Women's Hospital, Boston, MA, USA.
  • 6 Harvard Skin Disease Research Center, Harvard Medical School, Boston, MA, USA.
  • 7 Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA.
  • 8 Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA, USA.
  • 9 Department of Pediatrics, Harvard Medical School, Boston, MA, USA.
  • 10 The Center for Microbes, Development and Health, Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, China. xingliu@ips.ac.cn.
  • 11 The Joint Center for Infection and Immunity, Guangzhou Institute of Pediatrics, Guangzhou Women and Children's Medical Center, Guangzhou, China. xingliu@ips.ac.cn.
  • 12 The Joint Center for Infection and Immunity, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, China. xingliu@ips.ac.cn.
  • # Contributed equally.
Abstract

Gasdermins, a family of five pore-forming proteins (GSDMA-GSDME) in humans expressed predominantly in the skin, mucosa and immune sentinel cells, are key executioners of inflammatory cell death (Pyroptosis), which recruits immune cells to Infection sites and promotes protective immunity1,2. Pore formation is triggered by gasdermin cleavage1,2. Although the proteases that activate GSDMB, C, D and E have been identified, how GSDMA-the dominant gasdermin in the skin-is activated, remains unknown. Streptococcus pyogenes, also known as group A Streptococcus (GAS), is a major skin pathogen that causes substantial morbidity and mortality worldwide3. Here we show that the GAS cysteine protease SpeB virulence factor triggers keratinocyte Pyroptosis by cleaving GSDMA after Gln246, unleashing an active N-terminal fragment that triggers Pyroptosis. Gsdma1 genetic deficiency blunts mouse immune responses to GAS, resulting in uncontrolled Bacterial dissemination and death. GSDMA acts as both a sensor and substrate of GAS SpeB and as an effector to trigger Pyroptosis, adding a simple one-molecule mechanism for host recognition and control of virulence of a dangerous microbial pathogen.

Figures