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Title: A novel mechanism of MHC class I downregulation by the viral KK3 ubiquitin E3 ligase of Kaposi's sarcoma-associated herpes virus
Author: Duncan, L.
Awarding Body: University of Cambridge
Current Institution: University of Cambridge
Date of Award: 2004
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The MHC class I antigen presentation pathway plays a critical role in defense against intracellular pathogens. Viruses use many different strategies to evade the class I machinery. The subject of my thesis is the characterisation of the KK3 protein from the Kaposi’s Sarcoma-associated herpes virus. I show that KK3 subverts the MHC class I antigen presentation pathway by downregulating MHC class I complexes from the plasma membrane via a novel mechanism. The 322 amino acid KK3 is a type III transmembrane protein that contains an N-terminal RING-variant domain and a unique C-terminal tail with a number of predicted SH3 domains, myristoylation and phosphorylation sites. The RING-variant motif is characterised by seven cysteines and one histidine in the order C4HC3 and share both sequence and structural homology with RING finger domains found in a class of cellular E3 ubiquitin ligases. Following homodimerisation, KK3 associates with MHC class I molecules and promotes their ubiquitination after export from the edoplasmic reticulum. Ubiquitination requires the KK3 RING-variant domain and provides the signal for class I internalisation at the plasma membrane via clathrin-coated vesicles. Once internalised, ubiquitinated MHC class I molecules are targeted in a TSG101 dependent manner to the late endocytic pathway for degradation. KK3 is the first viral gene product that subverts the trafficking of a host protein via the ubiquitin-dependent endosomal sorting machinery. KK3 and its mouse specific homologue MK3 of MHV-68 are the first members of a new subclass of E3 ubiquitin ligases containing a RING-variant domain. The RING-variant domain can be found in a number of viral cellular homologues. Following structural and functional comparison of classical RING domain E3 ligases with the RING-variant proteins, the emergence of a new class of transmembrane E3 ubiquitin ligases is predicted.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available