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

doi:10.1038/s41467-020-15576-3

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

Chemistry

Research output: Contribution to journal › Article › peer-review

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 language	English (US)
Article number	1786
Journal	Nature communications
Volume	11
Issue number	1
DOIs	https://doi.org/10.1038/s41467-020-15576-3
State	Published - Dec 1 2020

ASJC Scopus subject areas

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

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10.1038/s41467-020-15576-3

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@article{27de947af206461985364be8c97ad6a0,

title = "Modulation of virus-induced NF-κB signaling by NEMO coiled coil mimics",

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{\textquoteright}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.",

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

note = "Funding Information: The authors thank Andrea Gardner at Weill Cornell Medicine for technical assistance, and Fraser Glickman and Jeanne Chiaravalli at the High throughput screening center at the Rockefeller University for the help with the small molecule screen. The confocal live microscopy was performed at the Imaging Core Facility at Weill Cornell Medicine. These studies were funded by NIH (R01CA154228 and R01CA103646 to E.C., R35GM130333 to P.S.A., R01GM120736 to P.S.A. and Y.Z, and R35GM127040 to Y.Z.), the Leukemia and Lymphoma Society (SCOR 7012-16 to E.C.). J.S. is thankful for her support by the Lymphoma Research foundation postdoctoral fellowship grant. M.G.W. is grateful for Margaret-Strauss-Kramer and Margaret and Herman Sokol Predoctoral Fellowships from the NYU Chemistry Department and the NYU Dean{\textquoteright}s Dissertation Fellowship. Publisher Copyright: {\textcopyright} 2020, The Author(s).",

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doi = "10.1038/s41467-020-15576-3",

language = "English (US)",

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AU - Sadek, Jouliana

AU - Wuo, Michael G.

AU - Rooklin, David

AU - Hauenstein, Arthur

AU - Hong, Seong Ho

AU - Gautam, Archana

AU - Wu, Hao

AU - Zhang, Yingkai

AU - Cesarman, Ethel

AU - Arora, Paramjit S.

N1 - Funding Information: The authors thank Andrea Gardner at Weill Cornell Medicine for technical assistance, and Fraser Glickman and Jeanne Chiaravalli at the High throughput screening center at the Rockefeller University for the help with the small molecule screen. The confocal live microscopy was performed at the Imaging Core Facility at Weill Cornell Medicine. These studies were funded by NIH (R01CA154228 and R01CA103646 to E.C., R35GM130333 to P.S.A., R01GM120736 to P.S.A. and Y.Z, and R35GM127040 to Y.Z.), the Leukemia and Lymphoma Society (SCOR 7012-16 to E.C.). J.S. is thankful for her support by the Lymphoma Research foundation postdoctoral fellowship grant. M.G.W. is grateful for Margaret-Strauss-Kramer and Margaret and Herman Sokol Predoctoral Fellowships from the NYU Chemistry Department and the NYU Dean’s Dissertation Fellowship. Publisher Copyright: © 2020, The Author(s).

PY - 2020/12/1

Y1 - 2020/12/1

N2 - 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.

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

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