title: Chlamydiainterfere with an interaction between the mannose-6-phosphate receptor and sorting nexins to counteract host restriction.
abstract: Chlamydia trachomatisis 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. trachomatisinfection 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.
authors.affiliation: Department of Medicine, University of California, San Francisco, San Francisco, United States.
authors.forename: Cherilyn A
authors.identifier: 0000-0001-7702-3938
authors.initials: CA
authors.lastname: Elwell
authors.affiliation: Department of Medicine, University of California, San Francisco, San Francisco, United States.
authors.forename: Nadine
authors.identifier: 0000-0002-0771-0721
authors.initials: N
authors.lastname: Czudnochowski
authors.affiliation: Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, United States.
authors.forename: John
authors.initials: J
authors.lastname: von Dollen
authors.affiliation: Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, United States.
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Johnson
authors.affiliation: Department of Medicine, University of California, San Francisco, San Francisco, United States.
authors.forename: Rachel
authors.initials: R
authors.lastname: Nakagawa
authors.affiliation: Department of Medicine, University of California, San Francisco, San Francisco, United States.
authors.forename: Kathleen
authors.initials: K
authors.lastname: Mirrashidi
authors.affiliation: Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, United States.|QB3, California Institute for Quantitative Biosciences, San Francisco, United States.|Gladstone Institutes, San Francisco, United States.
authors.forename: Nevan J
authors.initials: NJ
authors.lastname: Krogan
authors.affiliation: Department of Medicine, University of California, San Francisco, San Francisco, United States.|Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, United States.
authors.forename: Joanne N
authors.initials: JN
authors.lastname: Engel
authors.affiliation: Department of Medicine, University of California, San Francisco, San Francisco, United States.
authors.forename: Oren S
authors.identifier: 0000-0002-5736-4388
authors.initials: OS
authors.lastname: Rosenberg
mesh_terms: D000818:Animals; D001426:Bacterial Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D002692:Chlamydia trachomatis / Q000276:immunology* / Q000502:physiology*; D018360:Crystallography, X-Ray; D004252:DNA Mutational Analysis; D054884:Host-Pathogen Interactions; D057131:Immune Evasion; D051379:Mice; D008958:Models, Molecular; D011487:Protein Conformation; D025941:Protein Interaction Mapping; D017527:Receptor, IGF Type 2 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D058305:Sorting Nexins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
chemical_list: D001426:Bacterial Proteins; D017527:Receptor, IGF Type 2; C402667:SNX5 protein, human; D058305:Sorting Nexins
keywords: Chlamydia trachomatis; bacterial pathogenesis; biophysics; human; infectious disease; mannose-6-phosphate receptor; microbiology; retromer; sorting nexin; structural biology