It is increasingly clear that the biological functions of a transcription factor cannot be fully understood solely on the basis of protein-coding genes that fall under its control. Many transcription factors regulate expression of miRNAs, which affect the cell by modulating translation and stability of mRNAs. The identities and the roles of NF-kappaB-regulated miRNAs have been attracting research interest for a long time. We revisited this issue in a system with controlled expression of one of the key regulators of NF-kappaB, RIPK1. Several regulated miRNAs were identified, including miR-146a, miR-215 and miR-497. The miRNAs were also inducible by IL-1beta, but not when NF-kappaB activity was repressed by mutant IkappaBalpha. The presence of a miR-497 site was predicted in the 3'-UTR of IKBKB gene, which encodes IKKbeta. Using appropriately engineered reporters, we confirmed that this site can be a target of suppressive action of miR-497. Our findings suggest that NF-kappaB controls expression of a miRNA, which may reduce production of IKKbeta. Considering the role of IKKbeta in the canonical pathway of NF-kappaB activation, our observations may indicate a new mechanism that modulates the magnitude of such activation, as well as the propensity of a cell to engage canonical vs. non-canonical pathways.
Mechtler, P., Singhal, R., Kichina, J. V., Bard, J. E., Buck, M. J., & Kandel, E. S. (2015). MicroRNA analysis suggests an additional level of feedback regulation in the NF-κB signaling cascade. Oncotarget, 6(19). https://doi.org/10.18632/oncotarget.4005