Circuitry of nuclear factor kB signaling

Acknowledgements We apologize to the many researchers whose work we have not been able to discuss in this limited review. A. H. thanks X.-F. Qin and T. H. Leung for longstanding collaboration and communication of unpublished results, G. Ghosh for figures of protein structures, and E. A. Komives, G. Ghosh, and V. Sivakumar for insightful discussions. Summary: Over the past few years, the transcription factor nuclear factor (NF)-kB and the proteins that regulate it have emerged as a signaling system of pre-eminent importance in human physiology and in an increasing number of pathologies. While NF-kB is present in all differentiated cell types, its discovery and early characterization were rooted in understanding B-cell biology. Significant research efforts over two decades have yielded a large body of literature devoted to understanding NF-kB’s functioning in the immune system. NF-kB has been found to play roles in many different compartments of the immune system during differentiation of immune cells and development of lymphoid organs and during immune activation. NF-kB is the nuclear effector of signaling pathways emanating from many receptors, including those of the inflammatory tumor necrosis factor and Toll-like receptor superfamilies. With this review, we hope to provide historical context and summarize the diverse physiological functions of NF-kB in the immune system before focusing on recent advances in elucidating the molecular mechanisms that mediate cell type-specific and stimulusspecific functions of this pleiotropic signaling system. Understanding the genetic regulatory circuitry of NF-kB functionalities involves system-wide measurements, biophysical studies, and computational modeling.