Chlamydia interfere with an interaction between the mannose-6-phosphate receptor and sorting nexins to counteract host restriction

Abstract

Chlamydia trachomatis is an obligate intracellular pathogen that resides in a membrane-bound compartment, the inclusion. The bacteria secrete a unique class of proteins, Incs, which insert into the inclusion membrane and modulate the host-bacterium interface. We previously reported that IncE binds specifically to the Sorting Nexin 5 Phox domain (SNX5-PX) and disrupts retromer trafficking. Here, we present the crystal structure of the SNX5-PX:IncE complex, showing IncE bound to a unique and highly conserved hydrophobic groove on SNX5. Mutagenesis of the SNX5-PX:IncE binding surface disrupts a previously unsuspected interaction between SNX5 and the cation-independent mannose-6-phosphate receptor (CI-MPR). Addition of IncE peptide inhibits the interaction of CI-MPR with SNX5. Finally, C. trachomatis infection interferes with the SNX5:CI-MPR interaction, suggesting that IncE and CI-MPR are dependent on the same binding surface on SNX5. Our results provide new insights into retromer assembly and underscore the power of using pathogens to discover disease-related cell biology.

Article and author information

Author details

  1. Cherilyn A Elwell

    Department of Medicine, University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Nadine Czudnochowski

    Department of Medicine, University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. John von Dollen

    Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Jeffrey R Johnson

    Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Rachel Nakagawa

    Department of Medicine, University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Kathleen Mirrashidi

    Department of Medicine, University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Nevan J Krogan

    Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Joanne N Engel

    Department of Medicine, University of California, San Francisco, San Francisco, United States
    For correspondence
    joanne.engel@ucsf.edu
    Competing interests
    The authors declare that no competing interests exist.
  9. Oren S Rosenberg

    Department of Medicine, University of California, San Francisco, San Francisco, United States
    For correspondence
    oren.rosenberg@ucsf.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5736-4388

Funding

National Institutes of Health (K08AI091656)

  • Oren S Rosenberg

National Institutes of Health (AI073770)

  • Joanne N Engel

National Institutes of Health (AI105561)

  • Joanne N Engel

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

Reviewing Editor

  1. Suzanne R Pfeffer, Stanford University School of Medicine, United States

Publication history

  1. Received: October 26, 2016
  2. Accepted: February 26, 2017
  3. Accepted Manuscript published: March 2, 2017 (version 1)
  4. Version of Record published: March 23, 2017 (version 2)

Copyright

© 2017, Elwell 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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  1. Cherilyn A Elwell
  2. Nadine Czudnochowski
  3. John von Dollen
  4. Jeffrey R Johnson
  5. Rachel Nakagawa
  6. Kathleen Mirrashidi
  7. Nevan J Krogan
  8. Joanne N Engel
  9. Oren S Rosenberg
(2017)
Chlamydia interfere with an interaction between the mannose-6-phosphate receptor and sorting nexins to counteract host restriction
eLife 6:e22709.
https://doi.org/10.7554/eLife.22709

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