Targeted regulation of a cell signaling pathway

NF-kB signaling mediates critical cellular functions such as inflammation, immunity, and survival, and is regulated by the kinase IKK. Using a structure-function approach, the authors showed that a conserved linear motif underlies the specificity of recognition of the IKK catalytic core for its substrates in NF-kB signaling pathways. This mechanism represents a promising therapeutic target for a broad spectrum of pathologies, ranging from cancer to autoimmune diseases. This work is published in the journal Nature communications.

Using an approach based on in vitro and in cellulo experiments, the authors identified a novel small linear motif (or SLiM), which is conserved in substrates of the canonical and alternative NF-kB pathways only, and which ensures the docking of IKK catalytic dimers. This protein-protein interaction then promotes efficient substrate phosphorylation, which occurs in a conserved sequence distinct from the motif identified in this study.

NF-kB signaling is impaired in a broad spectrum of human diseases, making IKK a major therapeutic target. All IKK-targeting molecules developed so far inhibit enzymatic activity, thus acting on all cellular functions of IKK, whether NF-kB dependent or not. This translates into a lack of specificity and high toxicity of these inhibitors. The authors therefore exploited the knowledge on the docking mechanism to design a bivalent ligand derived from the docking motif. This ligand, which binds specifically to the IKK groove, inhibits substrate phosphorylation and downstream molecular events at the level of the canonical NF-kB pathway. This paves the way for the design of specific modulators of NF-kB signaling based on a protein-protein interaction inhibition approach.

For more information, read the news published on the CNRS Biology website.