1. Structural Biology and Molecular Biophysics
  2. Microbiology and Infectious Disease

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

  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  Is a corresponding author
  9. Oren S Rosenberg  Is a corresponding author
  1. University of California, San Francisco, United States
https://doi.org/10.7554/eLife.22709
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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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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.

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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.

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

Share this article

https://doi.org/10.7554/eLife.22709

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Further reading

    1. Structural Biology and Molecular Biophysics
    2. Microbiology and Infectious Disease

    Structural basis for the hijacking of endosomal sorting nexin proteins by Chlamydia trachomatis

    Blessy Paul, Hyun Sung Kim ... Brett M Collins
    Research Article Updated

    During infection chlamydial pathogens form an intracellular membrane-bound replicative niche termed the inclusion, which is enriched with bacterial transmembrane proteins called Incs. Incs bind and manipulate host cell proteins to promote inclusion expansion and provide camouflage against innate immune responses. Sorting nexin (SNX) proteins that normally function in endosomal membrane trafficking are a major class of inclusion-associated host proteins, and are recruited by IncE/CT116. Crystal structures of the SNX5 phox-homology (PX) domain in complex with IncE define the precise molecular basis for these interactions. The binding site is unique to SNX5 and related family members SNX6 and SNX32. Intriguingly the site is also conserved in SNX5 homologues throughout evolution, suggesting that IncE captures SNX5-related proteins by mimicking a native host protein interaction. These findings thus provide the first mechanistic insights both into how chlamydial Incs hijack host proteins, and how SNX5-related PX domains function as scaffolds in protein complex assembly.