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

Elife. 2017 Mar 2;6:e22709. doi: 10.7554/eLife.22709.


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.

Keywords: Chlamydia trachomatis; bacterial pathogenesis; biophysics; human; infectious disease; mannose-6-phosphate receptor; microbiology; retromer; sorting nexin; structural biology.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Bacterial Proteins / chemistry
  • Bacterial Proteins / genetics
  • Bacterial Proteins / metabolism*
  • Chlamydia trachomatis / immunology*
  • Chlamydia trachomatis / physiology*
  • Crystallography, X-Ray
  • DNA Mutational Analysis
  • Host-Pathogen Interactions*
  • Immune Evasion*
  • Mice
  • Models, Molecular
  • Protein Conformation
  • Protein Interaction Mapping
  • Receptor, IGF Type 2 / chemistry
  • Receptor, IGF Type 2 / genetics
  • Receptor, IGF Type 2 / metabolism*
  • Sorting Nexins / chemistry
  • Sorting Nexins / genetics
  • Sorting Nexins / metabolism*


  • Bacterial Proteins
  • Receptor, IGF Type 2
  • SNX5 protein, human
  • Sorting Nexins