5lde
Crystal structure of a vFLIP-IKKgamma stapled peptide dimer
Structural highlights
FunctionVFLIP_HHV8P Plays a role in the modulation of host signaling pathways by acting as an activator of both the classic and the alternative NF-kappa-B pathways. Thereby, initiates an important range of cellular processes to promote cell survival, proliferation and protection from apoptosis.[1] [2] [3] SPG2_STRSG Publication Abstract from PubMedPrimary 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, IKKgamma (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-IKKgamma interaction both in cells and in vitro can be achieved using IKKgamma 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-kappaB pathway that requires a physical interaction between ks-vFLIP and the IKK kinase modulatory subunit IKKgamma. 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 IKKgamma is pivotal in conferring resistance to apoptosis. Additionally, we show that the ks-vFLIP-IKKgamma 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. IKKgamma mimetic peptides block the resistance to apoptosis associated with KSHV infection.,Briggs LC, Chan AWE, Davis CA, Whitelock N, Hotiana HA, Baratchian M, Bagneris C, Selwood DL, Collins MK, Barrett TE J Virol. 2017 Sep 20. pii: JVI.01170-17. doi: 10.1128/JVI.01170-17. PMID:28931678[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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