Mechanistic insights into the activation of the IKK kinase complex by the Kaposi’s Sarcoma Herpes virus oncoprotein vFLIP

Bagneris, Claire and Senthil Kumar, Swathi and Baratchian, M. and Britt, H. and Tufa, A. and Britt, H. and Thalassinos, Kostas and Collins, M. and Barrett, Tracey (2022) Mechanistic insights into the activation of the IKK kinase complex by the Kaposi’s Sarcoma Herpes virus oncoprotein vFLIP. Journal of Biological Chemistry 298 (6), p. 102012. ISSN 0021-9258.

Abstract

Constitutive activation of the canonical NF-B signaling pathway is a major factor in Kaposi’s Sarcoma Herpes virus (KSHV) pathogenesis where it is essential for the survival of primary effusion lymphoma (PEL). Central to this process is persistent upregulation of the inhibitor of B kinase (IKK) kinase complex by the virally encoded oncoprotein vFLIP. Although the physical interaction between vFLIP and the IKK kinase regulatory component essential for persistent activation, IKK, has been well characterized, it remains unclear how the kinase subunits are rendered active mechanistically. Using a combination of cell-based assays, biophysical techniques, and structural biology, we demonstrate here that vFLIP alone is sufficient to activate the IKK kinase complex. Furthermore, we identify weakly stabilised, high molecular weight vFLIP-IKK assemblies that are key to the activation process. Taken together, our results are the first to reveal that vFLIP induced NF-B activation pivots on the formation of structurally specific vFLIP-IKK multimers which have an important role in rendering the kinase subunits active through a process of autophosphorylation. This mechanism of NF-B activation is in contrast to those utilised by endogenous cytokines and cellular FLIP homologues.

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