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

Michelle Vincendeau, Kamyar Hadian, Ana C. Messias, Jara K. Brenke, Jenny Halander, Richard Griesbach, Ute Greczmiel, Arianna Bertossi, Ralf Stehle, Daniel Nagel, Katrin Demski, Hana Velvarska, Dierk Niessing, Arie Geerlof, Michael Sattler, Daniel Krappmann

Publikation: Beitrag in FachzeitschriftArtikelBegutachtung

25 Zitate (Scopus)

Abstract

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.

OriginalspracheEnglisch
Aufsatznummer18934
FachzeitschriftScientific Reports
Jahrgang6
DOIs
PublikationsstatusVeröffentlicht - 7 Jan. 2016

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