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

Abstract

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.DOI: http://dx.doi.org/10.7554/eLife.22311.001

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.…”

“…Despite these studies, functions of the C-terminus of RidL remain unclear117 . Since many multiple-domain Legionella effectors have related functions in each of their domains, RidL likely regulates endosomal trafficking through other mechanisms, such as posttranslational modifications of retromer or related proteins.Another pathogenic protein that has been extensively characterized is the Chlamydial effector protein IncE110,[118][119][120][121] . Chlamydiae infection leads to human blindness, respiratory and genital tract diseases.…”

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.…”