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.DOI: http://dx.doi.org/10.7554/eLife.22709.001

Endosomal receptor trafficking: Retromer and beyond

“…Another pathogenic protein that has been extensively characterized is the Chlamydial effector protein IncE. Chlamydiae infection leads to human blindness, respiratory and genital tract diseases.…”

“…IncE is one of the effector proteins localized on the inclusion membrane, which specifically interacts with SNX5/SNX6 and inhibits retromer‐ and SNX5/SNX6‐mediated endosomal trafficking. Structural studies from 3 different groups revealed that IncE binds to a conserved hydrophobic groove in the PX domain of SNX5. Although the exact inhibitory mechanisms exerted by IncE remain to be determined, 2 observations indicate that IncE may function through interfering with the interaction between SNX5 and its cargo, such as IGFR1 and CI‐MPR (Figure B).…”

“…Structural studies from 3 different groups revealed that IncE binds to a conserved hydrophobic groove in the PX domain of SNX5. Although the exact inhibitory mechanisms exerted by IncE remain to be determined, 2 observations indicate that IncE may function through interfering with the interaction between SNX5 and its cargo, such as IGFR1 and CI‐MPR (Figure B). First, a SNX5 mutant unable to bind to IncE shows decreased binding to IGFR1 and CI‐MPR.…”

“…Although the exact inhibitory mechanisms exerted by IncE remain to be determined, 2 observations indicate that IncE may function through interfering with the interaction between SNX5 and its cargo, such as IGFR1 and CI‐MPR (Figure B). First, a SNX5 mutant unable to bind to IncE shows decreased binding to IGFR1 and CI‐MPR. Second, overexpression of IncE reduces co‐localization of CI‐M6PR with VPS35, and inhibits the delivery of CI‐MPR to the TGN.…”

IncV, a FFAT motif-containing Chlamydia protein, tethers the endoplasmic reticulum to the pathogen-containing vacuole

“…However, it is unknown if Inc proteins can also act as structural components to bring and maintain the ER and the inclusion membrane in close apposition. C. trachomatis encodes more than 50 putative Incs and only some of them have known functions in C. trachomatis infection (24,28,(31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41)(42)(43). Recently, Mirrashidi et al (37) determined the Inc-human interactome from uninfected cells expressing C. trachomatis Inc proteins.…”