Modulation of virus-induced NF-κB signaling by NEMO coiled coil mimics

Jouliana Sadek, Michael G. Wuo, David Rooklin, Arthur Hauenstein, Seong Ho Hong, Archana Gautam, Hao Wu, Yingkai Zhang, Ethel Cesarman, Paramjit S. Arora

Research output: Contribution to journalArticle

Abstract

Protein-protein interactions featuring intricate binding epitopes remain challenging targets for synthetic inhibitors. Interactions of NEMO, a scaffolding protein central to NF-κB signaling, exemplify this challenge. Various regulators are known to interact with different coiled coil regions of NEMO, but the topological complexity of this protein has limited inhibitor design. We undertook a comprehensive effort to block the interaction between vFLIP, a Kaposi’s sarcoma herpesviral oncoprotein, and NEMO using small molecule screening and rational design. Our efforts reveal that a tertiary protein structure mimic of NEMO is necessary for potent inhibition. The rationally designed mimic engages vFLIP directly causing complex disruption, protein degradation and suppression of NF-κB signaling in primary effusion lymphoma (PEL). NEMO mimic treatment induces cell death and delays tumor growth in a PEL xenograft model. Our studies with this inhibitor reveal the critical nexus of signaling complex stability in the regulation of NF-κB by a viral oncoprotein.

Original languageEnglish (US)
Article number1786
JournalNature communications
Volume11
Issue number1
DOIs
StatePublished - Dec 1 2020

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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    Sadek, J., Wuo, M. G., Rooklin, D., Hauenstein, A., Hong, S. H., Gautam, A., Wu, H., Zhang, Y., Cesarman, E., & Arora, P. S. (2020). Modulation of virus-induced NF-κB signaling by NEMO coiled coil mimics. Nature communications, 11(1), [1786]. https://doi.org/10.1038/s41467-020-15576-3