7pdj

Publication Abstract from PubMed

Constitutive activation of the canonical NF-kappaB signaling pathway is a major factor in Kaposi's sarcoma-associated herpes virus pathogenesis where it is essential for the survival of primary effusion lymphoma. Central to this process is persistent upregulation of the inhibitor of kappaB kinase (IKK) complex by the virally encoded oncoprotein vFLIP. Although the physical interaction between vFLIP and the IKK kinase regulatory component essential for persistent activation, IKKgamma, 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 stabilized, high molecular weight vFLIP-IKKgamma assemblies that are key to the activation process. Taken together, our results are the first to reveal that vFLIP-induced NF-kappaB activation pivots on the formation of structurally specific vFLIP-IKKgamma multimers which have an important role in rendering the kinase subunits active through a process of autophosphorylation. This mechanism of NF-kappaB activation is in contrast to those utilized by endogenous cytokines and cellular FLIP homologues.

Mechanistic insights into the activation of the IKK kinase complex by the Kaposi's sarcoma herpes virus oncoprotein vFLIP.,Bagneris C, Senthil Kumar SL, Baratchian M, Britt HM, Assafa TE, Thalassinos K, Collins MK, Barrett TE J Biol Chem. 2022 Jun;298(6):102012. doi: 10.1016/j.jbc.2022.102012. Epub 2022 , May 5. PMID:35525271^[4]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.