Activation of NF-kappa B by the Kaposi%26apos;s Sarcoma-Associated Herpesvirus K15 Protein Involves Recruitment of the NF-kappa B-Inducing Kinase, I kappa B Kinases, and Phosphorylation of p65

作者：Havemeier Anika; Gramolelli Silvia; Pietrek Marcel; Jochmann Ramona; Stuerzl Michael; Schulz Thomas F^*

来源：Journal of Virology, 2014, 88(22): 13161-13172.

DOI：10.1128/JVI.01766-14

Kaposi%26apos;s sarcoma herpesvirus (KSHV) (or human herpesvirus 8) is the cause of Kaposi%26apos;s sarcoma, primary effusion lymphoma (PEL), and the plasma cell variant of multicentric Castleman%26apos;s disease (MCD). The transmembrane K15 protein, encoded by KSHV, has been shown to activate NF-kappa B 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 (PLC gamma) and to contribute to KSHV-induced angiogenesis. Here we investigate how the K15 protein activates the NF-kappa B pathway. We show that activation of NF-kappa B involves the recruitment of NF-kappa B-inducing kinase (NIK) and IKK alpha/beta to result in the phosphorylation of p65/RelA on Ser536. A K15 mutant devoid in NIK/IKK recruitment fails to activate NF-kappa B 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-kappa B pathway. %26lt;br%26gt;IMPORTANCE %26lt;br%26gt;KSHV K15 is a viral protein involved in the activation of proinflammatory and angiogenic pathways. Previous studies reported that K15 can activate the NF-kappa B pathway. Here we show the molecular mechanism underlying the activation of this signaling pathway by K15, which involves direct recruitment of the NF-kappa B-inducing kinase NIK to K15 as well as NIK-mediated NF-kappa B p65 phosphorylation on Ser536. K15 is the first viral protein shown to activate NF-kappa B through direct recruitment of NIK. These results indicate a new mechanism whereby a viral protein can manipulate the NF-kappa B pathway.

• 出版日期2014-11