Triggered by viral infection, the PRR-mediated immune response pathways are highly robust and complicated with the involvement of multiple, transiently assembled protein complexes that function in an interconnected and phenotypic manner. This complex assembly and diverse pathways demand new technology capable of systematically profiling those critical pathway components in more sensitive and precise approaches. We have previously demonstrated the unique strength of our discovery proteomics platform in identifying/profiling novel pathway constituents, including those dynamic protein-protein interactions (PPIs) and post-translational modifications (PTMs) involved in the regulation of the initiation, progression and termination of PRR-mediated immune signaling. We also showed that these results from the proteomic dissection of PRR-mediated pathways could guide and streamline in-depth functional analyses using conventional genetic, cell biology, and immunology approaches, thereby enlarging the scope of mechanistic understanding of the host immune response. Leveraging this extensive experience, the overall objective of this shared resource Core B is to enumerate the constituents of the subsequent signaling pathways caused by the interaction of innate immune PRRs with viruses. All quantitative proteomic analyses of PPIs and PTMs, the two major pathway operators, as well as virus-induced protein translocations, can be performed comparatively for infected subjects versus non-infected controls or at different infection stages in either global or subcellular compartments or in organelle-specific fashion. Various quantitative schemes including AACT/SILAC, ITRAQ, and label-free quantitation will be complimentarily used in our experiments for not only cell lines, but also primary cells or tissues. Additionally, we will be significantly involved in guiding sample preparation in all Projects, particularly those associated with newly developed techniques of proteomics. Results will generate multiple hypotheses (i.e. discovery of novel proteins, PPIs or PTMs) in both interconnected and efficient manners to guide concurrently the discovery and elucidation of novel biologies, pathways and mechanisms. Specifically by applying the state-of-the-art technology of quantitative proteomics, we will (1) dissect either global or pathway-specific protein-protein interaction networks (interactome) involved in the PRR-mediated immune response to viral infection, and (2) identify/profile global or interactome-specific post-translational modifications (PTMs) including phosphorylation, acetylation, and ubiquitination involved in the PRR-mediated immune response to viral infection.
PRR-mediated intracellular signaling pathways play regulatory roles in the host immune response to viral infection. The Proteomics Pathway Discovery Core will use a varity of quantitative proteomics methodologies to identify and profile novel components of virus-inducible PRR-mediated signaling pathways. Results will guide and streamline new pathway characterization as defined by Projects 1-3 for revealing the immune mechanisms that lead to immunopathology versus a protective immune response during virus infection.
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