Separation-of-function mutants reveal the NF-κB-independent involvement of IκBα in the regulation of stem cell and oncogenic programs

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.06.21.545928v1?rss=1 Authors: Alvarez-Villanueva, D., Galan, L., Bertran, j., Floor, M., Sole, L., Lobo-Jarne, T., Maqueda, M., Rajbhandari, R., Marruecos, L., Villa, J., Bredel, M., Bigas, A., Espinosa, L. Abstract: We previously demonstrated that the NF-{kappa}B inhibitor I{kappa}B binds the chromatin together with PRC2 to regulate a subset of developmental- and stem cell-related genes. This alternative function has been elusive in both physiological and disease conditions because of the predominant role of I{kappa}B as a negative regulator of NF-{kappa}B. We here uniquely characterize specific residues of I{kappa}B that allow the generation of separation-of-function (SOF) mutants that are defective for either NF-{kappa}B-related (SOF{Delta}NF-{kappa}B) or chromatin-related (SOF{Delta}H2A,H4) activities. Expression of I{kappa}B SOF{Delta}NF-{kappa}B, but not SOF{Delta}H2A/H4, is sufficient to negatively regulate a specific stemness program in intestinal cells, thus rescuing the differentiation blockage imposed by I{kappa}B deficiency. In contrast, full I{kappa}B activity is required for regulating clonogenic/tumor-initiating activity of colorectal cancer cells. Our data indicate that SOF mutants represent an exclusive tool for studying I{kappa}B functions in physiology and disease, and identified I{kappa}B as a robust prognosis biomarker for human cancer. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC