Streptococcal pyrogenic exotoxin B cleaves GSDMA and triggers pyroptosis - Nature.com

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.

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Fig. 1: The GAS virulence factor SpeB triggers lytic death of skin epithelial cells.
Fig. 2: SpeB triggers pyroptosis in a GSDMA-dependent manner.
Fig. 3: SpeB directly cleaves GSDMA after Gln246.
Fig. 4: Gsdma1 deficiency blunts host anti-GAS immunity.

Data availability

All data supporting the findings of this study are included in this manuscript and its supplementary information. Source data are provided with this paper.

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Acknowledgements

We thank V. Nizet for sharing S. pyogenes isolate M1T1 strain 5448 and its isogenic mutant strains (ΔspeB, covR/S−, ΔcepA and Δmac variants) as well as SpeB constructs, Z. Zhang for providing S. pyogenes M9, M12 amd M73 strains, C. Wang for providing Phage-Flag vector, and Y. Chen for providing a modified pET vector with an N-terminal 6×His-SUMO tag. This work was supported by National Key R&D Program of China (2020YFA0509600), National Natural Science Foundation of China (32122034, 31972897), Key Research Program of the Chinese Academy of Sciences (ZDBS-LY-SM008), Shanghai Pilot Program for Basic Research–Chinese Academy of Sciences, Shanghai Branch (JCYJ-SHFY-2021-009), Strategic Priority Research Program of Chinese Academy of Sciences (XDB29030300), Shanghai Municipal Science and Technology Major Project (2019SHZDZX02) (X.L.), NIH R01CA240955 and R01AI39914 (J.L.), NIH R01AI127654 (T.S.K.) and China Postdoctoral Science Foundation (2019M650193), Guangzhou Science and Technology Project (202102020093) (W.D.).

Author information

Author notes

  1. These authors contributed equally: Wanyan Deng, Yang Bai, Fan Deng, Youdong Pan

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

    Wanyan Deng, Yang Bai, Fan Deng, Zengzhang Zheng, Rui Min, Zeyu Wu, Wu Li & Xing Liu

  2. The Joint Center for Infection and Immunity, Guangzhou Institute of Pediatrics, Guangzhou Women and Children's Medical Center, Guangzhou, China

    Wanyan Deng, Zengzhang Zheng, Wu Li & Xing Liu

  3. The Joint Center for Infection and Immunity, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, China

    Wanyan Deng, Zengzhang Zheng, Wu Li & Xing Liu

  4. University of Chinese Academy of Sciences, Beijing, China

    Yang Bai, Fan Deng, Rui Min & Zeyu Wu

  5. Department of Dermatology, Brigham and Women's Hospital, Boston, MA, USA

    Youdong Pan & Thomas S. Kupper

  6. Harvard Skin Disease Research Center, Harvard Medical School, Boston, MA, USA

    Youdong Pan & Thomas S. Kupper

  7. Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA

    Shenglin Mei

  8. Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA, USA

    Rui Miao, Zhibin Zhang & Judy Lieberman

  9. Department of Pediatrics, Harvard Medical School, Boston, MA, USA

    Rui Miao, Zhibin Zhang & Judy Lieberman

Authors
  1. Wanyan Deng
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  2. Yang Bai
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  3. Fan Deng
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  4. Youdong Pan
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  5. Shenglin Mei
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  6. Zengzhang Zheng
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  7. Rui Min
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  8. Zeyu Wu

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