Viral inhibitor of apoptosis vFLIP/K13 protects endothelial cells against superoxide-induced cell death.
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-1beta-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-kappaB. 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-kappaB, 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.
Thurau
Mathias
M
Department of Surgery, Division of Molecular and Experimental Surgery, University of Erlangen-Nuremberg, Erlangen, Germany.
Marquardt
Gaby
G
Gonin-Laurent
Nathalie
N
Weinländer
Kristina
K
Naschberger
Elisabeth
E
Jochmann
Ramona
R
Alkharsah
Khaled R
KR
Schulz
Thomas F
TF
Thome
Margot
M
Neipel
Frank
F
Stürzl
Michael
M
D016923:Cell Death; D002460:Cell Line; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000187:drug effects* / Q000821:virology*; D020869:Gene Expression Profiling; D019288:Herpesvirus 8, Human / Q000502:physiology*; D006801:Humans; D016328:NF-kappa B / Q000378:metabolism; D020543:Proteome / Q000032:analysis; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D013482:Superoxide Dismutase / Q000096:biosynthesis / Q000235:genetics; D013481:Superoxides / Q000633:toxicity*; D015854:Up-Regulation; D014764:Viral Proteins / Q000502:physiology*
D016328:NF-kappa B; D020543:Proteome; D012333:RNA, Messenger; D014764:Viral Proteins; C481275:viral FLIP protein, Human herpesvirus 8; D013481:Superoxides; D013482:Superoxide Dismutase