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

Vincendeau, Michelle; Hadian, Kamyar; Messias, Ana C.; Brenke, Jara K.; Halander, Jenny; Griesbach, Richard; Greczmiel, Ute; Bertossi, Arianna; Stehle, Ralf; Nagel, Daniel; Demski, Katrin; Velvarska, Hana; Niessing, Dierk; Geerlof, Arie; Sattler, Michael; Krappmann, Daniel (2016): Inhibition of Canonical NF-kappa B Signaling by a Small Molecule Targeting NEMO-Ubiquitin Interaction. In: Scientific Reports, Vol. 6, 18934

Abstract

The I kappa B kinase (IKK) complex acts as the gatekeeper of canonical NF-kappa B signaling, thereby regulating immunity, inflammation and cancer. It consists of the catalytic subunits IKK alpha and IKK beta and the regulatory subunit NEMO/IKK gamma.. Here, we show that the ubiquitin binding domain (UBAN) in NEMO-is essential for IKK/NF-kappa B activation in response to TNF alpha, but not IL-1 beta 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-kappa B activation upon UBAN-dependent TNF alpha and TCR/CD28, but not UBAN-independent IL-1 beta stimulation. Moreover, iNUB was selectively killing lymphoma cells that are addicted to chronic B-cell receptor triggered IKK/NF-kappa B activation. Thus, iNUB disrupts the NEMO-ubiquitin protein-protein interaction interface and thereby inhibits physiological and pathological NF-kappa B signaling.

• Item Type: Journal article
• Faculties: Medicine > Anatomic Institute
• Subjects: 600 Technology > 610 Medicine and health
• ISSN: 2045-2322
• Language: English