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The 11 th International Workshop on KSHV & Related Agents, Birmingham, UK Virus-Cell Interactions I Abstract 23 INSIGHTS INTO KSHV ACTIVATION OF THE IKK SIGNALOSOME: CRYSTAL STRUCTURE OF A VFLIP-IKKγ COMPLEX. Claire Bagnéris, Alexander V Ageichik, Nora Cronin, Bonnie Wallace, Mary Collins, Chris Boshoff, Gabriel Waksman and Tracey Barrett 1 1 Institute of Structural and Molecular Biology, School of Crystallography, Birkbeck College, Malet Street, London WC1E 7HX, UK. Abstract During the latent phase of Kaposi Sarcoma Herpes virus (KSHV) infection, a limited number of genes are expressed that are pivotal to viral propagation and survival. Amongst them is ks-vFLIP whose over-expression has been directly linked to Kaposi Sarcoma (KS) and other lymphoproliferative malignancies. ks-vFLIP shares considerable homology with the human cellular FLIPs that have a key anti-apoptotic role, but by contrast operates via a mechanism that involves subversion of the canonical NF-κB transcriptional pathway (implicated in diverse cellular processes that include immune activation and cellular growth). This is achieved through a direct interaction with IKKγ, the regulatory component of the IKK complex or signalosome, and results in the normally tightly regulated pathway being rendered constitutively active. As a consequence, the expression of genes associated with anti-apoptosis, inflammation and oncogenesis are aberrantly up-regulated. In order to establish the molecular basis underpinning ks-vFLIP constitutive activation of the canonical NF-κB pathway, we have determined the crystal structure of ks-vFLIP bound to an IKKγ fragment incorporating the ks-vFLIP recognition motif. This first structure of a ks-vFLIP-IKKγ complex reveals an extensive ks-vFLIP-IKKγ interface that has been probed using site directed mutagenesis to confirm the roles of key amino acids in mediating the ks-vFLIP-IKKγ interaction. In addition, these have been shown to be essential for ks-vFLIP induced activation of the canonical NF-κB pathway. Our structure thus provides a framework for the design of novel therapeutics aimed at the treatment of KS and related pathologies. Presenting author Email: t.barrett@mail.cryst.bbk.ac.uk 46
The 11 th International Workshop on KSHV & Related Agents, Birmingham, UK Virus-Cell Interactions I Abstract 24 THE VIRAL INHIBITOR OF APOPTOSIS VFLIP/K13 PROTECTS ENDOTHELIAL CELLS AGAINST SUPEROXIDE - INDUCED CELL DEATH Michael Stürzl(1), Gaby Sander(1), Nathalie Gonin-Laurent(1), Kristina Weinländer(1), Elisabeth Naschberger(1), Ramona Jochmann(1), Khaled R. Alkharsah(2), Thomas F. Schulz(2), Margot Thome(3), Frank Neipel(4) and Mathias Thurau(1) (1) Department of Surgery, Division of Molecular and Experimental Surgery, University of Erlangen-Nuremberg, Erlangen, Germany. (2) Medical School Hannover, Department of Virology, Hannover, Germany. (3) Department of Biochemistry, University of Lausanne, Epalinges, Switzerland. (4) Institute for Clinical and Molecular Virology, University of Erlangen-Nuremberg, Erlangen, Germany Abstract Human herpesvirus-8 (HHV-8) is the etiological agent of Kaposi’s sarcoma (KS). The gene K13 of HHV-8 encodes for the anti-apoptotic viral FLICE-inhibitory protein vFLIP/K13. It is expressed in the latent phase of the viral life cycle and its expression in KS lesions is inversely related to the rate of apoptosis. The mechanisms by which vFLIP/K13 inhibits cell death have to be elucidated. By using a comparative proteome analysis we identified manganese superoxide dismutase (MnSOD), a mitochondrial antioxidant and an important anti-apoptotic enzyme, as the most strongly up-regulated protein by vFLIP/K13 in endothelial cells. MnSOD expression was also up-regulated in endothelial cells upon infection with HHV-8. The induction of MnSOD expression by vFLIP/K13 was dependent on NF-kappaB activation, occurred in a cell intrinsic manner, and correlated with decreased intracellular superoxide accumulation and increased resistance of endothelial cells against superoxide-induced death. These findings show a novel function of vFLIP/K13 in cell death inhibition and in regulation of mitochondrial redox-balance via the upregulation of MnSOD expression. Presenting author Email: michael.stuerzl@uk-erlangen.de 47
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