Abstract
SUMMARYAdaptive immunity and the five vertebrate NF-κB/Rel family members first appeared in cartilaginous fish, suggesting that divergence and specialization within the NF-κB family helped facilitate the evolution of adaptive immunity. One specialized function of the NF-κB c-Rel protein in macrophages is the activation ofIl12b, which encodes a key regulator of T-cell development. We found that c-Rel is a far more potent regulator ofIl12bthan of any other inducible genes in macrophages, with c-Rel regulation ofIl12bdependent on its heightened intrinsic DNA-binding affinity. c-Rel homodimers regulateIl12btranscription in part via motifs with little resemblance to canonical NF-κB motifs. ChIP-seq experiments further defined distinct c-Rel DNA-binding preferences genome-wide, and X-ray crystallography of a c-Rel/RelA chimeric protein identified key amino acid changes that support the unique c-Rel properties. Unexpectedly, these changes, along with the c-Rel/RelA binding affinity differences, were largely restricted to mammalian species. Together, our findings reveal how a transcription factor family member can undergo a structural transition at a late stage of vertebrate evolution, resulting in an increased intrinsic DNA binding affinity and with clear functional consequences, presumably to support the increasing complexity of immune regulation.
Publisher
Cold Spring Harbor Laboratory