doi: 10.1093/gbe/evab289.
Rel/NF-κB Transcription Factors Emerged at the Onset of Opisthokonts
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- PMID:34999783
- PMCID: PMC8763368
- DOI: 10.1093/gbe/evab289
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Rel/NF-κB Transcription Factors Emerged at the Onset of Opisthokonts
Michelle M Leger et al. Genome Biol Evol..
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Abstract
The Rel/NF-κB transcription factor family has myriad roles in immunity, development, and differentiation in animals, and was considered a key innovation for animal multicellularity. Rel homology domain-containing proteins were previously hypothesized to have originated in a last common ancestor of animals and some of their closest unicellular relatives. However, key taxa were missing from previous analyses, necessitating a systematic investigation into the distribution and evolution of these proteins. Here, we address this knowledge gap by surveying taxonomically broad data from eukaryotes, with a special emphasis on lineages closely related to animals. We report an earlier origin for Rel/NF-κB proteins than previously described, in the last common ancestor of animals and fungi, and show that even in the sister group to fungi, these proteins contain elements that in animals are necessary for the subcellular regulation of Rel/NF-κB.
Keywords: NF-kappa B; NF-κB; Rel homology domain; opisthokonts; transcription factors.
© The Author(s) 2022. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.
Figures
Rel/NF-κB proteins emerged at the onset of Opisthokonta. (A) Domain architecture representation of members of the Rel/NF-κB, and NFAT protein families, IκB, and the IKK complex. Details of the represented features are shown in the domains and regions key. The Rel Homology Region, characteristic of Rel/NF-κB and NFAT proteins, contains conserved Rel homology DNA-binding (RHD DB) and dimerization domains (Dim) and, in the case of Rel/NF-κB proteins, an NLS (orange bar). Rel proteins also contain a C-terminal, serine-rich Transactivation Domain (Ct TAD) or a RelB TAD; and RelB proteins additionally possess an N-terminal leucine zipper domain (RelB LZ). The NF-κB1 precursor (p105) and NF-κB2 precursor (p100) contain a more centrally located GRR and C-terminal Death domain (Death). These precursors share with IκB proteins C-terminal ankyrin repeats (light green bars). Other domains present in IκB families include proline-, glutamic acid-, serine-, and threonine-rich regions (PEST). Key domains specific to NFAT proteins, include an N-terminal TAD (Nt TAD) inside an NHR, an NLS (orange bar) and C-terminal TAD (Ct TAD). PxIxIT and LxVP Calcineurin-binding motifs in the NHR are depicted with a magenta and a green bar, respectively. Domains for IKKalpha and beta include kinase domains (Kinase); ubiquitin-like domains (ULD); ubiquitin-binding domains (UBD); IQBAL scaffold dimerization domain (SDD); NEMO-binding domains (NBD). Domains for IKKγ/NF-κB essential modulator (NEMO) include NEMO domain (NEMO); UBD; leucine-zipper domains (LZ); and zinc finger domains (ZF). (B) Presence or absence of key Pfam domains analyzed in this study are represented in columns and color-coded according to genome or transcriptome data source (indicated in the Domain presence/absence key). The phylogenetic relationships of selected taxa are based on several recent phylogenomic studies (Torruella et al. 2015; Grau-Bové et al. 2017; Hehenberger et al. 2017; Tikhonenkov et al. 2020; Urrutia et al. 2021). Taxa are color-coded according to the Taxonomic Group key.
Rel homology domain phylogeny and domain architecture of Rel homology domain-containing proteins in NF-κB and NFAT families. Only SH-aLRT and nonparametric bootstrap support values above 80 and 60, respectively, are shown. Fully supported bipartitions are indicated with filled circles. Sequences are color-coded according to taxonomic group: red, Metazoa; yellow, Choanoflagellatea; orange, Filasterea; green, Ichthyosporea; and blue, Holomycota (Fungi and their closest relatives). The two side lengths of the collapsed NFAT clade are proportional to the distances between the node and its closest and furthest leaves. Schematic representation of Pfam domains and conserved regions related to Rel/NF-κB and NFAT proteins in the RHR are depicted to the right of each gene identifier; colors and abbreviations as in figure 1A. Domains or regions depicted in gray match domains or regions that were identified in previous Pfam versions or that share high sequence similarity in the protein alignment (at least four Lysine or Arginine residues in the case of NLS).
Partial multiple protein sequence alignment of key Rel/NF-κB domains in Opisthokonta. Partial protein sequence alignment (generated by MAFFT v7.299b E-INS-i multiple sequence alignment with the gap extension parameter set to 0) depicting the N- and C-terminal regions of the Rel homology DNA-binding domain, the N-terminal region of the Rel homology dimerization domain and the complete NLS. Background shading of individual amino acids reflects the degree of conservation at a given position; this degree of conservation is also depicted in the histogram shown below the alignment. Dashes indicate gaps in the alignment. Key DNA-binding amino acid residues in the recognition loop, residues comprising the complete linker region between the Rel homology DNA-binding domain and dimerization domain, and key residues in the NLS are highlighted in orange. The amino acid positions in the original sequences are shown to the left of each alignment series.
Evolution and diversification of Rel/NF-κB proteins in Opisthokonta. The Rel/NF-κB proteins originated along the Opisthokonta stem and diversified through gene duplication events and secondary losses and gains of key domains. Based on low sequence conservation of some regions and the lack of experimental information, we cannot rule out the possibility of TADs being present in other nonmetazoan species.
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