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

Abstract

The nuclear factor-kappa B (NF-kappaB) 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-kappaB is normally sequestered in the cytoplasm by a family of inhibitory proteins known as inhibitors of NF-kappaB (IkappaBs). The signal pathways leading to the liberation and nuclear accumulation of NF-kappaB, 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-kappaB 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-kappaB transcriptional activity. A non-Rel subunit of NF-kappaB, ribosomal protein S3 (RPS3), and numerous other nuclear regulators of NF-kappaB, including Akirin, Nurr1, SIRT6, and others, have recently been identified, unveiling novel and exciting layers of regulatory specificity for NF-kappaB in the nucleus. Further insights into the nuclear events that govern NF-kappaB function will deepen our understanding of the elegant control of its transcriptional activity and better inform the potential rational design of therapeutics for NF-kappaB-associated diseases.

Figure 1. The nuclear regulation of NF-κB

After it gains access to the nucleus, NF-κB transcriptional activity is elegantly controlled by a number of nuclear regulators, as illustrated in blue, including non-Rel subunits such as RPS3 (S3) within the NF-κB complex, proteins restricted to the nucleus or translocated from the plasma membrane, other transcription factors, and chromatin modifiers. Two distinct pathways to terminate the NF-κB transactivation, as illustrated in red, involve (I) IκB-mediated restitution of NF-κB to the cytoplasm and (II) ubiquitination-dependent nuclear degradation.