2. Academic Validation
  3. Enteroviral 3C protease activates the human NLRP1 inflammasome in airway epithelia

Enteroviral 3C protease activates the human NLRP1 inflammasome in airway epithelia

  • Science. 2020 Dec 4;370(6521):eaay2002. doi: 10.1126/science.aay2002.
Kim S Robinson 1 2,  Daniel Eng Thiam Teo  # 3,  Kai Sen Tan  # 4,  Gee Ann Toh  # 3,  Hsiao Hui Ong  # 4,  Chrissie Kaishi Lim 5,  Kenneth Lay 2 6,  Bijin Veonice Au 5,  Tian Sheng Lew 7,  Justin Jang Hann Chu 5 7,  Vincent Tak Kwong Chow 7,  De Yun Wang 4,  Franklin L Zhong 8 2 3 5,  Bruno Reversade 9 5 6 10 11
Affiliations

Affiliations

  • 1 Skin Research Institute of Singapore (SRIS), 8A Biomedical Grove, #06-06 Immunos, 138648, Singapore.
  • 2 Institute of Medical Biology, Agency of Science, Technological and Research, 8A Biomedical Grove, #06-06 Immunos, 138648, Singapore.
  • 3 Lee Kong Chian School of Medicine, Nanyang Technological University, 11 Mandalay Road, 308232, Singapore.
  • 4 Department of Otolaryngology, Infectious Diseases Translational Research Programme, Yong Loo Lin School of Medicine, National University Health System, National University of Singapore, 10 Medical Drive, 117597, Singapore.
  • 5 Institute of Molecular and Cell Biology, 61 Biopolis Drive, 138673, Singapore.
  • 6 Genome Institute of Singapore, 60 Biopolis Street, 138672, Singapore.
  • 7 Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University Health System, National University of Singapore, 10 Medical Drive, 117597, Singapore.
  • 8 Skin Research Institute of Singapore (SRIS), 8A Biomedical Grove, #06-06 Immunos, 138648, Singapore. franklin.zhong@ntu.edu.sg bruno@reversade.com.
  • 9 Institute of Medical Biology, Agency of Science, Technological and Research, 8A Biomedical Grove, #06-06 Immunos, 138648, Singapore. franklin.zhong@ntu.edu.sg bruno@reversade.com.
  • 10 Department of Paediatrics, Yong Loo Lin School of Medicine, National University Health System, National University of Singapore, 10 Medical Drive, 117597, Singapore.
  • 11 The Medical Genetics Department, Koç University School of Medicine, 34010 Istanbul, Turkey.
  • # Contributed equally.
PMID: 33093214 DOI: 10.1126/science.aay2002
Abstract

Immune sensor proteins are critical to the function of the human innate immune system. The full repertoire of cognate triggers for human immune sensors is not fully understood. Here, we report that human NACHT, LRR, and PYD domains-containing protein 1 (NLRP1) is activated by 3C proteases (3Cpros) of enteroviruses, such as human rhinovirus (HRV). 3Cpros directly cleave human NLRP1 at a single site between Glu130 and Gly131 This cleavage triggers N-glycine-mediated degradation of the autoinhibitory NLRP1 N-terminal fragment via the cullinZER1/ZYG11B complex, which liberates the activating C-terminal fragment. Infection of primary human airway epithelial cells by live human HRV triggers NLRP1-dependent inflammasome activation and interleukin-18 secretion. Our findings establish 3Cpros as a pathogen-derived trigger for the human NLRP1 inflammasome and suggest that NLRP1 may contribute to inflammatory diseases of the airway.

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