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    The Role of Rip2 Protein in the Nod Mediated Innate Immune Response: A Dissertation

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    Authors
    Yang, Yibin
    Faculty Advisor
    Michelle Kelliher, Ph.D.
    Academic Program
    Cancer Biology
    UMass Chan Affiliations
    Molecular, Cell and Cancer Biology
    Document Type
    Doctoral Dissertation
    Publication Date
    2010-04-16
    Keywords
    Receptor-Interacting Protein Serine-Threonine Kinase 2
    Nod2 Signaling Adaptor Protein
    Ubiquitin
    NF-kappa B
    Mycobacterium tuberculosis
    Amino Acids, Peptides, and Proteins
    Bacteria
    Enzymes and Coenzymes
    Hemic and Immune Systems
    Immunology and Infectious Disease
    
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    Abstract
    The Rip2 kinase contains a caspase recruitment domain (CARD) and has been implicated in the activation of the transcriptional factor NF-кB downstream of Nod-like receptors. However, how Rip2 mediates innate immune responses is still largely unclear. We show that Rip2 and IKK-γ become stably polyubiquitinated upon treatment of cells with the Nod2 ligand, muramyl dipeptide. We demonstrate a requirement for the E2 conjugating enzyme Ubc13, the E3 ubiquitin ligase Traf6 and the ubiquitin activated kinase Tak1 in Nod2-mediated NF-кB activation. We also show that M. tuberculosisinfection stimulates Rip2 polyubiquitination. Collectively, this study revealed that the Nod2 pathway is ubiquitin regulated and that Rip2 employs a ubiquitin-dependent mechanism to achieve NF-кB activation. We also demonstrate that intraphagosomal M. tuberculosis stimulates the cytosolic Nod2 pathway. We show that upon Mtb infection, Nod2 recognition triggers the expression of type I interferons in a Tbk1- and Irf5-dependent manner. This response is only partially impaired by the loss of Irf3 and therefore, differs fundamentally from those stimulated by bacterial DNA, which depends entirely on this transcription factor. This difference appears to result from the unusual peptidoglycan produced by mycobacteria, which we show is a uniquely potent agonist of the Nod2/Rip2/Irf5 pathway. Thus, the Nod2 system is specialized to recognize bacteria that actively perturb host membranes and is remarkably sensitive to Mycobacteria, perhaps reflecting the strong evolutionary pressure exerted by these pathogens on the mammalian immune system.
    DOI
    10.13028/hyk4-j832
    Permanent Link to this Item
    http://hdl.handle.net/20.500.14038/31807
    Rights
    Copyright is held by the author, with all rights reserved.
    ae974a485f413a2113503eed53cd6c53
    10.13028/hyk4-j832
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    Morningside Graduate School of Biomedical Sciences Dissertations and Theses

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