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Journal of Virology, January 2009, p. 598-611, Vol. 83, No. 2
0022-538X/09/$08.00+0     doi:10.1128/JVI.00629-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Viral Inhibitor of Apoptosis vFLIP/K13 Protects Endothelial Cells against Superoxide-Induced Cell Death{triangledown}

Mathias Thurau,1 Gaby Marquardt,1 Nathalie Gonin-Laurent,1,{dagger} Kristina Weinländer,1,{dagger} Elisabeth Naschberger,1 Ramona Jochmann,1 Khaled R. Alkharsah,2 Thomas F. Schulz,2 Margot Thome,3 Frank Neipel,4 and Michael Stürzl1*

Department of Surgery, Division of Molecular and Experimental Surgery, University of Erlangen-Nuremberg, Schwabachanlage 10, D-91054 Erlangen, Germany,1 Department of Virology, Medical School Hannover, Carl-Neuberg-Strasse 1, D-30625 Hannover, Germany,2 Department of Biochemistry, University of Lausanne, Chemin des Boveresses 155, CH-1066 Epalinges, Switzerland,3 Institute for Clinical and Molecular Virology, University of Erlangen-Nuremberg, Schlossgarten 4, D-91054 Erlangen, Germany4

Received 20 March 2008/ Accepted 28 October 2008

Human herpesvirus 8 (HHV-8) is the etiological agent of Kaposi's sarcoma (KS). HHV-8 encodes an antiapoptotic viral Fas-associated death domain-like interleukin-1β-converting enzyme-inhibitory protein (vFLIP/K13). The antiapoptotic activity of vFLIP/K13 has been attributed to an inhibition of caspase 8 activation and more recently to its capability to induce the expression of antiapoptotic proteins via activation of NF-{kappa}B. Our study provides the first proteome-wide analysis of the effect of vFLIP/K13 on cellular-protein expression. Using comparative proteome analysis, we identified manganese superoxide dismutase (MnSOD), a mitochondrial antioxidant and an important antiapoptotic enzyme, as the protein most strongly upregulated by vFLIP/K13 in endothelial cells. MnSOD expression was also upregulated in endothelial cells upon infection with HHV-8. Microarray analysis confirmed that MnSOD is also upregulated at the RNA level, though the differential expression at the RNA level was much lower (5.6-fold) than at the protein level (25.1-fold). The induction of MnSOD expression was dependent on vFLIP/K13-mediated activation of NF-{kappa}B, occurred in a cell-intrinsic manner, and was correlated with decreased intracellular superoxide accumulation and increased resistance of endothelial cells to superoxide-induced death. The upregulation of MnSOD expression by vFLIP/K13 may support the survival of HHV-8-infected cells in the inflammatory microenvironment in KS.

* Corresponding author. Mailing address: University of Erlangen-Nuremberg, Department of Surgery, Division of Molecular and Experimental Surgery, Schwabachanlage 10, D-91054 Erlangen, Germany. Phone: 49-9131-85-33109. Fax: 49-9131-85-32077. E-mail: michael.stuerzl{at}uk-erlangen.de

{triangledown} Published ahead of print on 5 November 2008.

{dagger} N.G.-L. and K.W. contributed equally to this work.

Journal of Virology, January 2009, p. 598-611, Vol. 83, No. 2
0022-538X/09/$08.00+0     doi:10.1128/JVI.00629-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.



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