1. Biochemistry and Chemical Biology
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Enterococcus faecium secreted antigen A generates muropeptides to enhance host immunity and limit bacterial pathogenesis

  1. Byungchul Kim
  2. Yen-Chih Wang
  3. Charles W Hespen
  4. Juliel Espinosa
  5. Jeanne Salje
  6. Kavita J Rangan
  7. Deena A Oren
  8. Jin Young Kang
  9. Virginia A Pedicord
  10. Howard C Hang  Is a corresponding author
  1. The Rockefeller University, United States
  2. University of Oxford, United Kingdom
Research Article
  • Cited 19
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Cite this article as: eLife 2019;8:e45343 doi: 10.7554/eLife.45343

Abstract

We discovered that Enterococcus faecium (E. faecium), a ubiquitous commensal bacterium, and its secreted peptidoglycan hydrolase (SagA) were sufficient to enhance intestinal barrier function and pathogen tolerance, but the precise biochemical mechanism was unknown. Here we show E. faecium has unique peptidoglycan composition and remodeling activity through SagA, which generates smaller muropeptides that more effectively activates nucleotide-binding oligomerization domain-containing protein 2 (NOD2) in mammalian cells. Our structural and biochemical studies show that SagA is a NlpC/p60-endopeptidase that preferentially hydrolyzes crosslinked Lys-type peptidoglycan fragments. SagA secretion and NlpC/p60-endopeptidase activity was required for enhancing probiotic bacteria activity against Clostridium difficile pathogenesis in vivo. Our results demonstrate that the peptidoglycan composition and hydrolase activity of specific microbiota species can activate host immune pathways and enhance tolerance to pathogens.

Data availability

All data generated or analyzed during this study are included in the manuscript and supporting files.Diffraction data have been deposited in PDB under the accession code 6B8C.

The following data sets were generated

Article and author information

Author details

  1. Byungchul Kim

    Laboratory of Chemical Biology and Microbial Pathogenesis, The Rockefeller University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Yen-Chih Wang

    Laboratory of Chemical Biology and Microbial Pathogenesis, The Rockefeller University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Charles W Hespen

    Laboratory of Chemical Biology and Microbial Pathogenesis, The Rockefeller University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Juliel Espinosa

    Laboratory of Chemical Biology and Microbial Pathogenesis, The Rockefeller University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2104-5331
  5. Jeanne Salje

    Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  6. Kavita J Rangan

    Laboratory of Chemical Biology and Microbial Pathogenesis, The Rockefeller University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Deena A Oren

    Structural Biology Resource Center, The Rockefeller University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Jin Young Kang

    Laboratory of Molecular Biophysics, The Rockefeller University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Virginia A Pedicord

    Laboratory of Chemical Biology and Microbial Pathogenesis, The Rockefeller University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Howard C Hang

    Laboratory of Chemical Biology and Microbial Pathogenesis, The Rockefeller University, New York, United States
    For correspondence
    hhang@rockefeller.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4053-5547

Funding

National Institute of General Medical Sciences (R01GM103593)

  • Byungchul Kim

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Kim Orth, HHMI/University of Texas Southwestern Medical Center, United States

Publication history

  1. Received: January 18, 2019
  2. Accepted: April 4, 2019
  3. Accepted Manuscript published: April 10, 2019 (version 1)
  4. Version of Record published: April 25, 2019 (version 2)

Copyright

© 2019, Kim et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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