Bagnéris, Claire;
Senthil Kumar, Swathi L;
Baratchian, Mehdi;
Britt, Hannah M;
Assafa, Tufa E;
Thalassinos, Konstantinos;
Collins, Mary K;
(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)
, Article 102012. 10.1016/j.jbc.2022.102012.
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Mechanistic insights into the activation of the IKK kinase complex by the Kaposi’s Sarcoma Herpes virus oncoprotein vFLIP.pdf Download (3MB) | Preview |
Abstract
Constitutive activation of the canonical NF-κB 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 κB 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, IKKγ, 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-IKKγ assemblies that are key to the activation process. Taken together, our results are the first to reveal that vFLIP induced NF-κB activation pivots on the formation of structurally specific vFLIP-IKKγ multimers which have an important role in rendering the kinase subunits active through a process of autophosphorylation. This mechanism of NF-κB activation is in contrast to those utilised by endogenous cytokines and cellular FLIP homologues.
| Type: | Article |
|---|---|
| Title: | Mechanistic insights into the activation of the IKK kinase complex by the Kaposi’s Sarcoma Herpes virus oncoprotein vFLIP |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1016/j.jbc.2022.102012 |
| Publisher version: | https://doi.org/10.1016/j.jbc.2022.102012 |
| Language: | English |
| Additional information: | Copyright © 2022 The authors. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). |
| Keywords: | KSHV, Canonical NF-kappaB pathway, vFLIP, IKK kinase, IKKgamma, IKKbeta, Constitutive activation |
| UCL classification: | UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Structural and Molecular Biology UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10148397 |
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