Activation of NF-ÎºB by the Kaposi's Sarcoma-Associated Herpesvirus K15 Protein Involves Recruitment of the NF-ÎºB-Inducing Kinase, IÎºB Kinases, and Phosphorylation of p65.

[primary effusion lymphoma]

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 K 15 protein , encoded by KSHV , has been shown to activate NF-ÎºB 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 (PLCÎ³ ) and to contribute to KSHV-induced angiogenesis . Here we investigate how the K 15 protein activates the NF-ÎºB pathway . We show that activation of NF-ÎºB involves the recruitment of NF-ÎºB-inducing kinase (NIK ) and IKK Î±/Î² to result in the phosphorylation of p 65 /RelA on Ser 536 . A K 15 mutant devoid in NIK /IKK recruitment fails to activate NF-ÎºB but remains proficient in the stimulation of both NFAT- and AP 1 -dependent promoters , showing that the structural integrity of the mutant K 15 protein has not been altered dramatically . Direct recruitment of NIK represents a novel way for a viral protein to activate and manipulate the NF-ÎºB pathway .K SHV K 15 is a viral protein involved in the activation of proinflammatory and angiogenic pathways . Previous studies reported that K 15 can activate the NF-ÎºB pathway . Here we show the molecular mechanism underlying the activation of this signaling pathway by K 15 , which involves direct recruitment of the NF-ÎºB-inducing kinase NIK to K 15 as well as NIK -mediated NF-ÎºB p 65 phosphorylation on Ser 536 . K 15 is the first viral protein shown to activate NF-ÎºB through direct recruitment of NIK . These results indicate a new mechanism whereby a viral protein can manipulate the NF-ÎºB pathway .