The Human Herpes Virus 8-encoded Viral FLICE Inhibitory Protein Physically Associates with and Persistently Activates the IκB Kinase Complex

The human herpesvirus 8 (HHV8, also called Kaposi's sarcoma-associated herpesvirus) has been linked to Kaposi's sarcoma and primary effusion lymphoma (PEL) in immunocompromised individuals. We demonstrate that PEL cell lines have a constitutively active NF-κB pathway, which is associated with persistent phosphorylation of IκBα. To elucidate the mechanism of NF-κB activation in PEL cell lines, we have investigated the role of viral FLICE inhibitory protein (vFLIP) in this process. We report that stable expression of HHV8 vFLIP in a variety of cell lines is associated with persistent NF-κB activation caused by constitutive phosphorylation of IκBα. HHV8 vFLIP gets recruited to a ∼700-kDa IκB kinase (IKK) complex and physically associates with IKKα, IKKβ, NEMO/IKKγ, and RIP. HHV8 vFLIP is incapable of activating NF-κB in cells deficient in NEMO/IKKγ, thereby suggesting an essential role of an intact IKK complex in this process. Our results suggest that HHV8 vFLIP might contribute to the persistent NF-κB activation observed in PEL cells by associating with and stimulating the activity of the cellular IKK complex.