IKKγ mimetic peptides block the resistance to apoptosis associated with KSHV infection

Briggs, L. C., Chan, A.W. E., Davis, C. A. , Whitelock, N., Hotiana, H. A., Baratchian, M., Bagnéris, C., Selwood, D. L., Collins, M. K. and Barrett, T. E. (2017) IKKγ mimetic peptides block the resistance to apoptosis associated with KSHV infection. Journal of Virology, 91(23), e01170-17. (doi: 10.1128/JVI.01170-17) (PMID:28931678) (PMCID:PMC5686756)

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Abstract

Primary effusion lymphoma (PEL) is a lymphogenic disorder associated with KSHV infection. Key to the survival and proliferation of PEL is the canonical NF-kB pathway that becomes constitutively activated following overexpression of the viral oncoprotein ks-vFLIP. This arises from its capacity to form a complex with the modulatory subunit of the IKK kinase, IKKγ (or NEMO) resulting in the overproduction of proteins that promote cellular survival and prevent apoptosis; both of which are important drivers of tumourigenesis. Using a combination of cell based and biophysical assays together with structural techniques, we show that the observed resistance to cell death is largely independent of autophagy or major death receptor signalling pathways and demonstrate that direct targeting of the ks-vFLIP-IKKγ interaction both in cells and in vitro can be achieved using IKKγ mimetic peptides. Our results further reveal that these peptides not only induce cell killing, but potently sensitise PEL to the pro-apoptotic agents tumour necrosis factor alpha and etoposide and are the first to confirm ks-vFLIP as a tractable target for the treatment of PEL and related disorders. IMPORTANCE: KSHV vFLIP (ks-vFLIP) has been shown to have a crucial role in cellular transformation where it is vital for the survival and proliferation of primary effusion lymphoma (PEL), an aggressive malignancy associated with infection that is resistant to the majority of chemotherapeutic drugs. It operates via subversion of the canonical NF-κB pathway that requires a physical interaction between ks-vFLIP and the IKK kinase modulatory subunit IKKγ. Whilst this interaction has been directly linked to protection against apoptosis, it is unclear whether the suppression of other cell death pathways implicated in ks-vFLIP pathogenesis are additional contributors. We demonstrate that the interaction between ks-vFLIP and IKKγ is pivotal in conferring resistance to apoptosis. Additionally, we show that the ks-vFLIP-IKKγ complex can be disrupted using peptides leading to direct killing and the sensitisation of PEL cells to pro-apoptotic agents. Our studies thus provide a framework for future therapeutic interventions.

Item Type:Articles
Additional Information:This work was supported by a CRUK drug discovery grant (Ref C19746/A9867) to DLS/TEB and a CRUK project grant (Ref C484/A12595) to MKC/TEB.
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Davis, Dr Chris
Authors: Briggs, L. C., Chan, A.W. E., Davis, C. A., Whitelock, N., Hotiana, H. A., Baratchian, M., Bagnéris, C., Selwood, D. L., Collins, M. K., and Barrett, T. E.
College/School:College of Medical Veterinary and Life Sciences > School of Infection & Immunity
College of Medical Veterinary and Life Sciences > School of Infection & Immunity > Centre for Virus Research
Journal Name:Journal of Virology
Publisher:American Society for Microbiology
ISSN:0022-538X
ISSN (Online):1098-5514
Published Online:20 September 2017
Copyright Holders:Copyright © 2017 The Authors
First Published:First published in Journal of Virology 91(23):e01170-17
Publisher Policy:Reproduced under a Creative Commons License

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