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 () and Paramjit S. Arora ()
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Jouliana Sadek: Weill Cornell Medical College
Michael G. Wuo: New York University
David Rooklin: New York University
Arthur Hauenstein: Harvard Medical School
Seong Ho Hong: New York University
Archana Gautam: Icahn School of Medicine at Mount Sinai
Hao Wu: Harvard Medical School
Yingkai Zhang: New York University
Ethel Cesarman: Weill Cornell Medical College
Paramjit S. Arora: New York University

Nature Communications, 2020, vol. 11, issue 1, 1-14

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-15576-3

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