Letter | Published:

Innate immune sensing of bacterial modifications of Rho GTPases by the Pyrin inflammasome

Nature volume 513, pages 237241 (11 September 2014) | Download Citation

Abstract

Cytosolic inflammasome complexes mediated by a pattern recognition receptor (PRR) defend against pathogen infection by activating caspase 1. Pyrin, a candidate PRR, can bind to the inflammasome adaptor ASC to form a caspase 1-activating complex1,2. Mutations in the Pyrin-encoding gene, MEFV, cause a human autoinflammatory disease known as familial Mediterranean fever3,4,5. Despite important roles in immunity and disease, the physiological function of Pyrin remains unknown. Here we show that Pyrin mediates caspase 1 inflammasome activation in response to Rho-glucosylation activity of cytotoxin TcdB6,7,8, a major virulence factor of Clostridium difficile, which causes most cases of nosocomial diarrhoea. The glucosyltransferase-inactive TcdB mutant loses the inflammasome-stimulating activity. Other Rho-inactivating toxins, including FIC-domain adenylyltransferases (Vibrio parahaemolyticus VopS and Histophilus somni IbpA) and Clostridium botulinum ADP-ribosylating C3 toxin, can also biochemically activate the Pyrin inflammasome in their enzymatic activity-dependent manner. These toxins all target the Rho subfamily and modify a switch-I residue. We further demonstrate that Burkholderia cenocepacia inactivates RHOA by deamidating Asn 41, also in the switch-I region, and thereby triggers Pyrin inflammasome activation, both of which require the bacterial type VI secretion system (T6SS). Loss of the Pyrin inflammasome causes elevated intra-macrophage growth of B. cenocepacia and diminished lung inflammation in mice. Thus, Pyrin functions to sense pathogen modification and inactivation of Rho GTPases, representing a new paradigm in mammalian innate immunity.

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Acknowledgements

We thank V. Dixit for providing knockout mice and anti-ASC antibody, D. Lyras for C. sordellii genomic DNA, J. Xiao for IbpA-Fic constructs, T. Iida for V. parahaemolyticus strain, M. Valvano for pDAI-SceI vector and H. Feng for TcdB B. megaterium expression system. We thank members of the Shao laboratory for discussions. The research was supported in part by an International Early Career Scientist grant from the Howard Hughes Medical Institute to F.S. This work was also supported by the National Basic Research Program of China 973 Program (2012CB518700), the Strategic Priority Research Program of the Chinese Academy of Sciences (XDB08020202) and China National Science Foundation Program for Distinguished Young Scholars (31225002) to F.S.

Author information

Author notes

    • Hao Xu
    •  & Jieling Yang

    These authors contributed equally to this work.

Affiliations

  1. National Institute of Biological Sciences, Beijing 102206, China

    • Hao Xu
    • , Jieling Yang
    • , Wenqing Gao
    • , Lin Li
    • , Peng Li
    • , Li Zhang
    • , Yi-Nan Gong
    • , Xiaolan Peng
    • , She Chen
    • , Fengchao Wang
    •  & Feng Shao
  2. National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China

    • Jieling Yang
    •  & Feng Shao
  3. Department of Biomedical Engineering, College of Engineering, Peking University, Beijing 100871, China

    • Jianzhong Jeff Xi
  4. National Institute of Biological Sciences, Beijing, Collaborative Innovation Center for Cancer Medicine, Beijing 102206, China

    • Feng Shao

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Contributions

F.S. conceived the study; H.X. and J.Y. performed the majority of experiments, assisted by W.G.; L.L., P.L., L.Z., Y.-N.G., X.P., J.J.X., S.C. and F.W. contributed reagents and analytic tools. H.X., J.Y. and F.S. analysed the data and wrote the manuscript. All authors discussed the results and commented on the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Feng Shao.

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https://doi.org/10.1038/nature13449

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