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Vincendeau, M. ; Hadian, K. ; Messias, A.C. ; Brenke, J.K. ; Halander, J. ; Griesbach, R.A. ; Greczmiel, U. ; Bertossi, A. ; Stehle, R. ; Nagel, D. ; Demski, K. ; Velvarska, H. ; Niessing, D. ; Geerlof, A. ; Sattler, M. ; Krappmann, D.

Inhibition of canonical NF-κB signaling by a small molecule targeting NEMO-ubiquitin interaction.

Sci. Rep. 6:18934 (2016)

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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 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-κB activation upon UBAN-dependent TNFα and TCR/CD28, but not UBAN-independent IL-1β stimulation. Moreover, iNUB was selectively killing lymphoma cells that are addicted to chronic B-cell receptor triggered IKK/NF-κB activation. Thus, iNUB disrupts the NEMO-ubiquitin protein-protein interaction interface and thereby inhibits physiological and pathological NF-κB signaling.

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