Dataset Information

Global Mapping of the Inc-Human Interactome Reveals that Retromer Restricts Chlamydia Infection.

ABSTRACT: Chlamydia trachomatis is a leading cause of genital and ocular infections for which no vaccine exists. Upon entry into host cells, C. trachomatis resides within a membrane-bound compartment—the inclusion—and secretes inclusion membrane proteins (Incs) that are thought to modulate the host-bacterium interface. To expand our understanding of Inc function(s), we subjected putative C. trachomatis Incs to affinity purification-mass spectroscopy (AP-MS). We identified Inc-human interactions for 38/58 Incs with enrichment in host processes consistent with Chlamydia's intracellular life cycle. There is significant overlap between Inc targets and viral proteins, suggesting common pathogenic mechanisms among obligate intracellular microbes. IncE binds to sorting nexins (SNXs) 5/6, components of the retromer, which relocalizes SNX5/6 to the inclusion membrane and augments inclusion membrane tubulation. Depletion of retromer components enhances progeny production, revealing that retromer restricts Chlamydia infection. This study demonstrates the value of proteomics in unveiling host-pathogen interactions in genetically challenging microbes.

SUBMITTER: Mirrashidi KM

PROVIDER: S-EPMC4540348 | biostudies-literature | 2015 Jul

REPOSITORIES: biostudies-literature

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Global Mapping of the Inc-Human Interactome Reveals that Retromer Restricts Chlamydia Infection.

Mirrashidi Kathleen M KM Elwell Cherilyn A CA Verschueren Erik E Johnson Jeffrey R JR Frando Andrew A Von Dollen John J Rosenberg Oren O Gulbahce Natali N Jang Gwendolyn G Johnson Tasha T Jäger Stefanie S Gopalakrishnan Anusha M AM Sherry Jessica J Dunn Joe Dan JD Olive Andrew A Penn Bennett B Shales Michael M Cox Jeffery S JS Starnbach Michael N MN Derre Isabelle I Valdivia Raphael R Krogan Nevan J NJ Engel Joanne J

Cell host & microbe 20150625 1

Chlamydia trachomatis is a leading cause of genital and ocular infections for which no vaccine exists. Upon entry into host cells, C. trachomatis resides within a membrane-bound compartment—the inclusion—and secretes inclusion membrane proteins (Incs) that are thought to modulate the host-bacterium interface. To expand our understanding of Inc function(s), we subjected putative C. trachomatis Incs to affinity purification-mass spectroscopy (AP-MS). We identified Inc-human interactions for 38/58 ...[more]

PMID: 26118995

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Project description:Malignant transformation is known to involve substantial rearrangement of the molecular genetic landscape of the cell. A common approach to analysis of these alterations is a reductionist one and consists of finding a compact set of differentially expressed genes or associated signaling pathways. However, due to intrinsic tumor heterogeneity and tissue specificity, biomarkers defined by a small number of genes/pathways exhibit substantial variability. As an alternative to compact differential signatures, global features of genetic cell machinery are conceivable. Global network descriptors suggested in previous works are, however, known to potentially be biased by overrepresentation of interactions between frequently studied genes-proteins. Here, we construct a cellular network of 74538 directional and differential gene expression weighted protein-protein and gene regulatory interactions, and perform graph-theoretical analysis of global human interactome using a novel, degree-independent feature-the normalized total communicability (NTC). We apply this framework to assess differences in total information flow between different cancer (BRCA/COAD/GBM) and non-cancer interactomes. Our experimental results reveal that different cancer interactomes are characterized by significant enhancement of long-range NTC, which arises from circulation of information flow within robustly organized gene subnetworks. Although enhancement of NTC emerges in different cancer types from different genomic profiles, we identified a subset of 90 common genes that are related to elevated NTC in all studied tumors. Our ontological analysis shows that these genes are associated with enhanced cell division, DNA replication, stress response, and other cellular functions and processes typically upregulated in cancer. We conclude that enhancement of long-range NTC manifested in the correlated activity of genes whose tight coordination is required for survival and proliferation of all tumor cells, and, thus, can be seen as a graph-theoretical equivalent to some hallmarks of cancer. The computational framework for differential network analysis presented herein is of potential interest for a wide range of network perturbation problems given by single or multiple gene-protein activation-inhibition.

Dataset Information

Global Mapping of the Inc-Human Interactome Reveals that Retromer Restricts Chlamydia Infection.

Publications

Global Mapping of the Inc-Human Interactome Reveals that Retromer Restricts Chlamydia Infection.

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