Molecular genetic analysis of human herpes virus 8-encoded viral FLICE inhibitory protein-induced NF-kappa B activation

作者：Matta H; Sun QM; Moses G; Chaudhary PM^*

来源：Journal of Biological Chemistry, 2003, 278(52): 52406-52411.

DOI：10.1074/jbc.M307308200

The human herpes virus 8 (HHV8)-encoded viral FLICE inhibitory protein (vFLIP), also known as K13, is known to activate the NF-kappaB pathway, a property not shared by other vFLIPs. Previous studies have demonstrated that HHV8 vFLIP K13 interacts with several cellular signaling proteins involved in NF-kappaB activation, such as receptor-interacting protein, NF-kappaB-inducing kinase, IkappaB kinase (IKK) 1, IKK2, and NF-kappaB essential modulator (NEMO). In this report we have used cell lines deficient in the above proteins to investigate the mechanism of NF-kappaB activation via HHV8 vFLIP K13. We demonstrate that receptor-interacting protein and NF-kappaB-inducing kinase are dispensable for vFLIP K13-induced NF-kappaB DNA binding and transcriptional activation. On the other hand, vFLIP K13-induced NF-kappaB DNA binding activity is significantly reduced, although not absent, in cells deficient in IKK1, IKK2, and NEMO. Furthermore, vFLIP K13-induced NF-kappaB transcriptional activity is only weakly present in IKK1-deficient cells and almost completely absent in those deficient in IKK2 and NEMO. HHV8 vFLIP K13-induced NF-kappaB activation in IKK1- and IKK2-deficient fibroblasts could be rescued by wild type but not by the kinase-inactive mutants of IKK1 and IKK2, respectively. Consistent with the above results, vFLIP K13-induced NF-kappaB activation could be effectively blocked by chemical inhibitors of the kinase activity of IKK1 and IKK2. Thus, a cooperative interaction of all three subunits of the IKK complex is required for maximal NF-kappaB activation via HHV8 vFLIP K13. Selective inhibitors of the IKK1 kinase activity may have a role in the treatment of disorders caused by abnormal NF-kappaB activation by HHV8 vFLIP K13.

• 出版日期2003-12-26