Activation of NF-κB by the Kaposi's sarcoma-associated herpesvirus K15 protein involves recruitment of the NF-κB-inducing kinase, IκB kinases, and phosphorylation of p65.

UNLABELLED: Kaposi's sarcoma herpesvirus (KSHV) (or human herpesvirus 8) is the cause of Kaposi's sarcoma, primary effusion lymphoma (PEL), and the plasma cell variant of multicentric Castleman's disease (MCD). The transmembrane K15 protein, encoded by KSHV, has been shown to activate NF-κB and the mitogen-activated protein kinases (MAPKs) c-jun-N-terminal kinase (JNK) and extracellular signal-regulated kinase (Erk) as well as phospholipase C gamma (PLCγ) and to contribute to KSHV-induced angiogenesis. Here we investigate how the K15 protein activates the NF-κB pathway. We show that activation of NF-κB involves the recruitment of NF-κB-inducing kinase (NIK) and IKK α/β to result in the phosphorylation of p65/RelA on Ser536. A K15 mutant devoid in NIK/IKK recruitment fails to activate NF-κB but remains proficient in the stimulation of both NFAT- and AP1-dependent promoters, showing that the structural integrity of the mutant K15 protein has not been altered dramatically. Direct recruitment of NIK represents a novel way for a viral protein to activate and manipulate the NF-κB pathway. IMPORTANCE: KSHV K15 is a viral protein involved in the activation of proinflammatory and angiogenic pathways. Previous studies reported that K15 can activate the NF-κB pathway. Here we show the molecular mechanism underlying the activation of this signaling pathway by K15, which involves direct recruitment of the NF-κB-inducing kinase NIK to K15 as well as NIK-mediated NF-κB p65 phosphorylation on Ser536. K15 is the first viral protein shown to activate NF-κB through direct recruitment of NIK. These results indicate a new mechanism whereby a viral protein can manipulate the NF-κB pathway.