Graduate Thesis Or Dissertation

 

An Analysis of Latent Membrane Protein-1 Signaling Complexes and Their Contribution to Epstein-Barr Virus Infection Public Deposited

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https://scholar.colorado.edu/concern/graduate_thesis_or_dissertations/pv63g0392
Abstract
  • In immunocompromised individuals, B cells infected with Epstein-Barr virus often display tumorigenic growth. One of the viral oncoproteins that contributes to this transformation is the latent membrane protein-1 (LMP-1), which constitutively mimics the signaling of ligand-dependent CD40, a tumor necrosis factor receptor. The experiments described in this dissertation were designed to elucidate the molecular mechanisms that underlie LMP-1's signaling potential. We investigated the relationships between LMP-1's subcellular localization, homo-oligomerization, comigration with detergent-resistant membranes, and its signaling outputs in order to bridge some of the gaps standing in the way of a unified theory of LMP-1 function. The data presented here are consistent with a working model where LMP-1's transmembrane domain drives local homo-oligomerization of small complexes, which in turn are assembled into larger megameric complexes, each with some capacity to perform LMP-1 signaling events. These megameric complexes, or LMP-1-enriched domains (LEDs), create an environment that is either particularly resistant to cholesterol-extraction by MβCD or that has cholesterol-independent DRM-like properties. Upon saturation of this pathway, nascent LMP-1 populates a new subset of juxtanuclear membrane compartments. LED formation is important for proper NFκB signaling and therefore is a promising target for the design of therapeutics against LMP-1-dependent EBV-associated diseases and malignancies.
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  • 2011
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  • 2019-11-16
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