Activation of the canononical NF-kB pathway by the Kaposi's sarcoma-associated herpes virus oncoprotein vFLIP

Senthil Kumar, Swathi Lakshmi (2024) Activation of the canononical NF-kB pathway by the Kaposi's sarcoma-associated herpes virus oncoprotein vFLIP. PhD thesis, Birkbeck, University of London.

Abstract

The oncoprotein vFLIP expressed by the Kaposi Sarcoma-associated Herpesvirus (KSHV) has the ability to cause the diseases Kaposi Sarcoma (KS), Primary Effusion Lymphoma and Multicentric Castleman Disease. vFLIP associates with the regulatory subunit of the IKK kinase complex, IKKγ, which leads to the constitutive activation of the canonical NF-κB pathway. This allows the virus to maintain long-term infection and evade apoptosis. Despite the interaction between vFLIP and IKKγ being characterized by a crystal structure, how this interaction led to the activation of the IKK complex was unknown. The structural and biophysical studies highlighted in this thesis indicate a novel mechanism of kinase oligomerization involving regions adjacent to but not overlapping with the main vFLIP-IKKγ interface originally identified. The studies detailed in this thesis also aimed to address the relationship between vFLIP and the A20 deubiquitinase, since its aberrant downregulation has also been implicated in KSHV pathogenesis. This study explored the interaction between vFLIP and two A20 domains involved in ubiquitin binding, zinc finger 7 and OTU, as well as investigating which region of vFLIP interacts with ubiquitin.

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