Abstract
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.
Highlights
Human herpes virus 8 (HHV8),1 known as Kaposi’s sarcoma-associated herpes virus, is a ␥-2 herpes virus that was originally isolated from Kaposi’s sarcoma and has been subsequently associated with several lymphoproliferative disorders, including primary effusion lymphoma or body cavity lym
We have previously demonstrated that human herpes virus 8 (HHV8) viral FLICE inhibitory protein (vFLIP) K13 possesses the unique ability to activate the NF-B pathway that is not shared by the vFLIP E8 from equine herpes virus 2 and the vFLIP MC159L from molluscum contagiosum virus [10]
Role of RIP in HHV8 vFLIP K13-induced NF-B Activation— RIP is a serine-threonine protein kinase, which has been shown to play an essential role in NF-B activation via TNF receptor 1 [13, 15]
Summary
Human herpes virus 8 (HHV8), known as Kaposi’s sarcoma-associated herpes virus, is a ␥-2 herpes virus that was originally isolated from Kaposi’s sarcoma and has been subsequently associated with several lymphoproliferative disorders, including primary effusion lymphoma or body cavity lym-. Proteins with two death effector domains have been encountered in other viruses as well and include MC159L and MC169 from the molluscum contagiosum virus and E8 from equine herpes virus 2 [7,8,9]. These virally encoded death effector domain-containing proteins are believed to protect virally infected cells from death receptorinduced apoptosis by blocking the recruitment and/or activation of caspase 8/FLICE [7,8,9]. We have focused on the functional contribution of the above interactions of vFLIP K13 to NF-B activation
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