Rel/NF-κB transcription factors and IκB inhibitors: Evolution from a unique common ancestor

Abstract

From the sequences of Rel/NF-κB and IκB proteins, we constructed an alignment of their Rel Homology Domain (RHD) and ankyrin repeat domain. Using this alignment, we performed tree reconstruction with both distance matrix and parsimony analysis and estimated the branching robustness using bootstrap resampling methods. We defined four subfamilies of Rel/NF-κB transcription factors: (i) cRel, RelA, RelB, Dorsal and Dif; (ii) NF-κB1 and NF-κB2; (iii) Relish and (iv) NF-AT factors, the most divergent members. Subfamilies I and II are clustered together whereas Relish diverged earlier than other Rel/NF-κB proteins. Three subfamilies of IκB inhibitors were also defined: (i) NF-κB1 and NF-κB2; (ii) close to subfamily I, the short IκB proteins IκBα, IκBβ and Bcl-3; (iii) Relish that diverged earlier than other IκB inhibitors. Our definition of groups and subfamilies fits to structural and functional features of the Rel/NF-κB and IκB proteins. We also showed that ankyrin repeats of NF-κB1, NF-κB2 and Relish are short IκB-specific ankyrin motifs. These proteins defining a link between Rel/NF-κB and IκB families, we propose that all these factors evolved from a common ancestral RHD-ankyrin structure within a unique superfamily, explaining the specificities of interaction between the different Rel/NF-κB dimers and the various IκB inhibitors.