
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 |
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Faculties: | Medicine > Anatomic Institute |
Subjects: | 600 Technology > 610 Medicine and health |
URN: | urn:nbn:de:bvb:19-epub-38151-4 |
ISSN: | 2045-2322 |
Language: | English |
Item ID: | 38151 |
Date Deposited: | 04. May 2017, 13:11 |
Last Modified: | 04. Nov 2020, 14:45 |