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Inhibition of Canonical NF-?B Signaling by a Small Molecule Targeting NEMO-Ubiquitin Interaction.


ABSTRACT: The I?B kinase (IKK) complex acts as the gatekeeper of canonical NF-?B signaling, thereby regulating immunity, inflammation and cancer. It consists of the catalytic subunits IKK? and IKK? and the regulatory subunit NEMO/IKK?. Here, we show that the ubiquitin binding domain (UBAN) in NEMO is essential for IKK/NF-?B activation in response to TNF?, but not IL-1? stimulation. By screening a natural compound library we identified an anthraquinone derivative that acts as an inhibitor of NEMO-ubiquitin binding (iNUB). Using biochemical and NMR experiments we demonstrate that iNUB binds to NEMOUBAN and competes for interaction with methionine-1-linked linear ubiquitin chains. iNUB inhibited NF-?B activation upon UBAN-dependent TNF? and TCR/CD28, but not UBAN-independent IL-1? stimulation. Moreover, iNUB was selectively killing lymphoma cells that are addicted to chronic B-cell receptor triggered IKK/NF-?B activation. Thus, iNUB disrupts the NEMO-ubiquitin protein-protein interaction interface and thereby inhibits physiological and pathological NF-?B signaling.

SUBMITTER: Vincendeau M 

PROVIDER: S-EPMC4703965 | biostudies-literature | 2016 Jan

REPOSITORIES: biostudies-literature

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The IκB kinase (IKK) complex acts as the gatekeeper of canonical NF-κB signaling, thereby regulating immunity, inflammation and cancer. It consists of the catalytic subunits IKKα and IKKβ and the regulatory subunit NEMO/IKKγ. Here, we show that the ubiquitin binding domain (UBAN) in NEMO is essential for IKK/NF-κB activation in response to TNFα, but not IL-1β stimulation. By screening a natural compound library we identified an anthraquinone derivative that acts as an inhibitor of NEMO-ubiquitin  ...[more]

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