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An analysis of latent membrane protein-1 signaling complexes and their contribution to Epstein-Barr virus infection

Posted on:2012-08-27Degree:Ph.DType:Dissertation
University:University of Colorado at BoulderCandidate:Takeshita, Ryan AkiraFull Text:PDF
GTID:1464390011968337Subject:Biology
Abstract/Summary:
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 methyl-beta-cyclodextrin 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 NFkappaB signaling and therefore is a promising target for the design of therapeutics against LMP-1-dependent EBV-associated diseases and malignancies.
Keywords/Search Tags:Signaling, LMP-1, Complexes, Membrane
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