The activity of NF-kB is tightly controlled in cells as it is the main controller of the transcription of genes that promote cellular survival and prevent programmed cell death. The cancer-causing Kaposi’s Sarcoma-associated Herpesvirus (KSHV) constitutively activates NF-kB in order to promote its own survival. This project aims to understand the mechanisms by which vFLIP, an essential virally encoded protein, is able to achieve persistent NF-kB activation . Concurrently, we will use computational and biophysical approaches to develop potent anti-virals and tool compounds to disrupt the protein-protein interactions shown to be crucial for viral proliferation and survival.
(1) Bagneris, C. Ageichik AV, Cronin N, Wallace B, Collins M, Boshoff C, Waksman G, Barrett T. Crystal structure of a vFlip-IKKgamma complex: insights into viral activation of the IKK signalosome. Mol Cell 30, 620-631, doi:S1097- 2765(08)00360-2 [pii] 10.1016/j.molcel.2008.04.029 (2008).
(2) Briggs, L. C, Chan AWE, Davis CA, Whitelock N, Hotiana HA, Baratchian M, Bagnéris C, Selwood DL, Collins MK, Barrett TE. IKKgamma mimetic peptides block the resistance to apoptosis associated with KSHV infection. J Virol, doi:10.1128/JVI.01170-17 (2017).
(3) Ding X, Xu J, Wang C, Feng Q, Wang Q, Yang Y, Lu H, Wang F, Zhu K, Li W, Yan Q, Gao SJ, Lu C. Suppression of the SAP18/HDAC1 complex by targeting TRIM56 and Nanog is essential for oncogenic viral FLICE-inhibitory protein-induced acetylation of p65/RelA, NF-κB activation, and promotion of cell invasion and angiogenesis. Cell Death and Differentation. https://doi.org/10.1038/s41418-018-0268-3. 2019.