期刊
JOURNAL OF VIROLOGY
卷 83, 期 2, 页码 598-611出版社
AMER SOC MICROBIOLOGY
DOI: 10.1128/JVI.00629-08
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资金
- Deutsche Forschungsgemeinschaft [DFG-SPP 1130, DFG-GK 1071, DFG 317/2-1]
- German Cancer Aid
- University of Erlangen-Nuremberg [D8/D9, AZ 05.11.13.1]
- IZKF [B11]
- Swiss National Science Foundation
- Swiss Cancer League (Oncosuisse)
- EU Integrated Project INCA [LSHC-CT-2005-018704]
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-1 beta-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.
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