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dc.contributor.advisorNeal Silverman, Ph.D.
dc.contributor.authorPaquette, Nicholas Paul
dc.date2022-08-11T08:08:42.000
dc.date.accessioned2022-08-23T16:04:54Z
dc.date.available2022-08-23T16:04:54Z
dc.date.issued2009-11-03
dc.date.submitted2010-01-04
dc.identifier.doi10.13028/pc1q-pe08
dc.identifier.urihttp://hdl.handle.net/20.500.14038/31773
dc.description.abstractInnate immunity is the first line of defense against invading pathogens. Vertebrate innate immunity provides both initial protection, and activates adaptive immune responses, including memory. As a result, the study of innate immune signaling is crucial for understanding the interactions between host and pathogen. Unlike mammals, the insect Drosophila melanogasterlack classical adaptive immunity, relying on innate immune signaling via the Toll and IMD pathways to detect and respond to invading pathogens. Once activated these pathways lead to the rapid and robust production of a variety of antimicrobial peptides. These peptides are secreted directly into the hemolymph and assist in clearance of the infection. The genetic and molecular tools available in the Drosophila system make it an excellent model system for studying immunity. Furthermore, the innate immune signaling pathways used by Drosophilashow strong homology to those of vertebrates making them ideal for the study of activation, regulation and mechanism. Currently a number of questions remain regarding the activation and regulation of both vertebrate and insect innate immune signaling. Over the past years many proteins have been implicated in mammalian and insect innate immune signaling pathways, however the mechanisms by which these proteins function remain largely undetermined. My work has focused on understanding the molecular mechanisms of innate immune activation in Drosophila. In these studies I have identified a number of novel protein/protein interactions which are vital for the activation and regulation of innate immune induction. This work shows that upon stimulation the Drosophila protein IMD is cleaved by the caspase-8 homologue DREDD. Cleaved IMD then binds the E3 ligase DIAP2 and promotes the K63-polyubiquitination of IMD and activation of downstream signaling. Furthermore the Yersinia pestis effector protein YopJ is able to inhibit the critical IMD pathway MAP3 kinase TAK1 by serine/threonine-acetylation of its activation loop. Lastly TAK1 signaling to the downstream Relish/NF-κB and JNK signaling pathways can be regulated by two isoforms of the TAB2 protein. This work elucidates the molecular mechanism of the IMD signaling pathway and suggests possible mechanisms of homologous mammalian systems, of which the molecular details remain unclear.
dc.language.isoen_US
dc.rightsCopyright is held by the author, with all rights reserved.
dc.subjectImmunity
dc.subjectInnate
dc.subjectI-kappa B Kinase
dc.subjectDrosophila Proteins
dc.subjectBacterial Proteins
dc.subjectYersinia pestis
dc.subjectAmino Acids, Peptides, and Proteins
dc.subjectBacteria
dc.subjectEnzymes and Coenzymes
dc.subjectHemic and Immune Systems
dc.titleCaspase Mediated Cleavage, IAP Binding, Ubiquitination and Kinase Activation : Defining the Molecular Mechanisms Required for Drosophila NF-кB Signaling: A Dissertation
dc.typeDoctoral Dissertation
dc.identifier.legacyfulltexthttps://escholarship.umassmed.edu/cgi/viewcontent.cgi?article=1445&context=gsbs_diss&unstamped=1
dc.identifier.legacycoverpagehttps://escholarship.umassmed.edu/gsbs_diss/444
dc.legacy.embargo2010-11-03T00:00:00-07:00
dc.identifier.contextkey1101570
refterms.dateFOA2022-08-24T03:20:23Z
html.description.abstract<p>Innate immunity is the first line of defense against invading pathogens. Vertebrate innate immunity provides both initial protection, and activates adaptive immune responses, including memory. As a result, the study of innate immune signaling is crucial for understanding the interactions between host and pathogen. Unlike mammals, the insect <em>Drosophila melanogaster</em>lack classical adaptive immunity, relying on innate immune signaling via the Toll and IMD pathways to detect and respond to invading pathogens. Once activated these pathways lead to the rapid and robust production of a variety of antimicrobial peptides. These peptides are secreted directly into the hemolymph and assist in clearance of the infection.</p> <p>The genetic and molecular tools available in the <em>Drosophila</em> system make it an excellent model system for studying immunity. Furthermore, the innate immune signaling pathways used by <em>Drosophila</em>show strong homology to those of vertebrates making them ideal for the study of activation, regulation and mechanism. Currently a number of questions remain regarding the activation and regulation of both vertebrate and insect innate immune signaling. Over the past years many proteins have been implicated in mammalian and insect innate immune signaling pathways, however the mechanisms by which these proteins function remain largely undetermined.</p> <p>My work has focused on understanding the molecular mechanisms of innate immune activation in <em>Drosophila</em>. In these studies I have identified a number of novel protein/protein interactions which are vital for the activation and regulation of innate immune induction. This work shows that upon stimulation the <em>Drosophila</em> protein IMD is cleaved by the caspase-8 homologue DREDD. Cleaved IMD then binds the E3 ligase DIAP2 and promotes the K63-polyubiquitination of IMD and activation of downstream signaling. Furthermore the <em>Yersinia pestis</em> effector protein YopJ is able to inhibit the critical IMD pathway MAP3 kinase TAK1 by serine/threonine-acetylation of its activation loop. Lastly TAK1 signaling to the downstream Relish/NF-κB and JNK signaling pathways can be regulated by two isoforms of the TAB2 protein. This work elucidates the molecular mechanism of the IMD signaling pathway and suggests possible mechanisms of homologous mammalian systems, of which the molecular details remain unclear.</p>
dc.identifier.submissionpathgsbs_diss/444
dc.contributor.departmentMedicine
dc.description.thesisprogramInterdisciplinary Graduate Program


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