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

• Published in: Nature communications Vol. 11; no. 1; p. 1786
• Main Authors: Sadek, Jouliana, Wuo, Michael G., Rooklin, David, Hauenstein, Arthur, Hong, Seong Ho, Gautam, Archana, Wu, Hao, Zhang, Yingkai, Cesarman, Ethel, Arora, Paramjit S.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 14.04.2020; Nature Publishing Group; Nature Portfolio
• Subjects: 119/118; 14; 14/34; 631/67/1858; 639/638/92/611; 64; 64/60; 82/47; 82/80; Animals; Apoptosis; Cell death; Cell Line; Cell survival; Circular Dichroism; Coils; Complexity; Effusion; Epitopes; Herpesvirus 8, Human - metabolism; Humanities and Social Sciences; Humans; I-kappa B Kinase - genetics; I-kappa B Kinase - metabolism; Inhibitors; Intracellular Signaling Peptides and Proteins - genetics; Intracellular Signaling Peptides and Proteins - metabolism; Lymphoma; Lymphoma, Primary Effusion - genetics; Lymphoma, Primary Effusion - metabolism; Male; Mice; Microscopy, Confocal; Models, Biological; multidisciplinary; NF-kappa B - metabolism; NF-κB protein; Primary effusion lymphoma; Protein interaction; Protein structure; Proteins; Regulators; Sarcoma; Scaffolding; Science; Science (multidisciplinary); Signal Transduction - genetics; Signal Transduction - physiology; Signaling; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Viruses; Xenograft Model Antitumor Assays; Xenografts; Xenotransplantation
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-020-15576-3

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. NF-κB signalling involves the scaffold protein NEMO, which can be bound by the oncoprotein vFLIP to promote cell survival and oncogenic transformation. Here the authors rationally engineer a tertiary protein mimic of NEMO to disrupt the vFLIP-NEMO interaction to induce cell death.