The nuclear signaling of NF-kappa B: current knowledge, new insights, and future perspectives

The nuclear factor-kappa B (NF-kappa B) transcription factor plays a critical role in diverse cellular processes associated with proliferation, cell death, development, as well as innate and adaptive immune responses. NF-kappa B is normally sequestered in the cytoplasm by a family of inhibitory proteins known as inhibitors of NF-kappa B (I kappa Bs). The signal pathways leading to the liberation and nuclear accumulation of NF-kappa B, which can be activated by a wide variety of stimuli, have been extensively studied in the past two decades. After gaining access to the nucleus, NF-kappa B must be actively regulated to execute its fundamental function as a transcription factor. Recent studies have highlighted the importance of nuclear signaling in the regulation of NF-kappa B transcriptional activity. A non-Rel subunit of NF-kappa B, ribosomal protein S3 (RPS3), and numerous other nuclear regulators of NF-kappa B, including Akirin, Nurr1, SIRT6, and others, have recently been identified, unveiling novel and exciting layers of regulatory specificity for NF-kappa B in the nucleus. Further insights into the nuclear events that govern NF-kappa B function will deepen our understanding of the elegant control of its transcriptional activity and better inform the potential rational design of therapeutics for NF-kappa B-associated diseases.