title: PPE38 of Mycobacterium marinum triggers the cross-talk of multiple pathways involved in the host response, as revealed by subcellular quantitative proteomics.
abstract: The PE/PPE family of proteins which are in high abundance in pathogenic species such as Mycobacterium tuberculosis and M. marinum , play the critical role in generating antigenic variation and evasion of host immune responses. However, little is known about their functional roles in mycobacterial pathogenesis. Previously, we found that PPE38 is associated with the virulence of mycobacteria, presumably by modulating the host immune response. To clarify the link between PPE38 and host response, we employed a subcellular, amino acid-coded mass tagging (AACT)/SILAC-based quantitative proteomic approach to determine the proteome changes during host response to M. marinum PPE38. As a result, 291 or 290 proteins were found respectively to be up- or down-regulated in the nucleus. Meanwhile, 576 upregulated and 272 downregulated proteins were respectively detected in the cytosol. The data of quantitative proteomic changes and concurrent biological validations revealed that M. marinum PPE38 could trigger extensive inflammatory responses in macrophages, probably through interacting with toll-like receptor 2 (TLR2). We also found that PPE38 may arrest MHC-1 processing and presentation in infected macrophages. Using bioinformatics tools to analyze global changes in the host proteome, we obtained a PPE38-respondor network involved in various transcriptional factors (TFs) and TF-associated proteins. The results of our systems investigation now indicate that there is cross-talk involving a broad range of diverse biological pathways/processes that coordinate the host response to M. marinum PPE38.
authors.affiliation: Key Laboratory of Medical Molecular Virology, Institute of Biomedical Sciences and Institute of Medical Microbiology, Shanghai Medical College, Fudan University, Shanghai 200032, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Wang
authors.forename: Dandan
authors.initials: D
authors.lastname: Dong
authors.forename: Siwei
authors.initials: S
authors.lastname: Tang
authors.forename: Xian
authors.initials: X
authors.lastname: Chen
authors.forename: Qian
authors.initials: Q
authors.lastname: Gao
mesh_terms: D000818:Animals; D017951:Antigen Presentation; D000942:Antigens, Bacterial / Q000502:physiology*; D001426:Bacterial Proteins / Q000502:physiology*; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D016000:Cluster Analysis; D016207:Cytokines / Q000378:metabolism; D005786:Gene Expression Regulation; D054884:Host-Pathogen Interactions; D008264:Macrophages / Q000276:immunology / Q000378:metabolism* / Q000382:microbiology; D051379:Mice; D019910:Mycobacterium marinum / Q000502:physiology*; D020543:Proteome / Q000378:metabolism*; D040901:Proteomics; D020239:Receptor Cross-Talk; D015398:Signal Transduction; D013347:Subcellular Fractions / Q000378:metabolism; D053719:Tandem Mass Spectrometry; D051195:Toll-Like Receptor 2 / Q000502:physiology; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D000942:Antigens, Bacterial; D001426:Bacterial Proteins; D016207:Cytokines; D020543:Proteome; C493486:Tlr2 protein, mouse; D051195:Toll-Like Receptor 2; D014157:Transcription Factors