title: Viral inhibitor of apoptosis vFLIP/K13 protects endothelial cells against superoxide-induced cell death.
abstract: 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.
authors.affiliation: Department of Surgery, Division of Molecular and Experimental Surgery, University of Erlangen-Nuremberg, Erlangen, Germany.
authors.forename: Mathias
authors.initials: M
authors.lastname: Thurau
authors.forename: Gaby
authors.initials: G
authors.lastname: Marquardt
authors.forename: Nathalie
authors.initials: N
authors.lastname: Gonin-Laurent
authors.forename: Kristina
authors.initials: K
authors.lastname: Weinländer
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Naschberger
authors.forename: Ramona
authors.initials: R
authors.lastname: Jochmann
authors.forename: Khaled R
authors.initials: KR
authors.lastname: Alkharsah
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Schulz
authors.forename: Margot
authors.initials: M
authors.lastname: Thome
authors.forename: Frank
authors.initials: F
authors.lastname: Neipel
authors.forename: Michael
authors.initials: M
authors.lastname: Stürzl
mesh_terms: 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*
chemical_list: D016328:NF-kappa B; D020543:Proteome; D012333:RNA, Messenger; D014764:Viral Proteins; C481275:viral FLIP protein, Human herpesvirus 8; D013481:Superoxides; D013482:Superoxide Dismutase