Protein citrullination was introduced into animals by horizontal gene transfer from cyanobacteria

Abstract

Protein post-translational modifications (PTMs) add an enormous amount of sophistication to biological systems but their origins are largely unexplored. Citrullination, a key regulatory mechanism in human physiology and pathophysiology, is particularly enigmatic in an evolutionary context. The citrullinating enzymes peptidylarginine deiminases (PADIs) are ubiquitous across vertebrates but absent from yeast, worms and flies. Here, we map the surprising evolutionary trajectory of PADIs into the animal lineage. We present strong phylogenetic support for a clade encompassing animal and cyanobacterial PADIs that excludes fungal and other bacterial homologues. The animal and cyanobacterial PADIs share unique, functionally relevant synapomorphies that are absent from all other homologues. Molecular clock calculations and sequence divergence analyses using the fossil record estimate the last common ancestor of the cyanobacterial and animal PADIs to be approximately 1 billion years old, far younger than the 3.35-4.52 billion years known to separate bacterial and eukaryotic lineages. Under an assumption of vertical descent, PADI sequence change is anachronistically slow during this evolutionary time frame, even when compared to mitochondrial proteins, products of likely endosymbiont gene transfer and some of the most highly conserved proteins in life. The consilience of evidence indicates that PADIs were introduced from cyanobacteria into animals by horizontal gene transfer (HGT). The ancestral cyanobacterial protein is enzymatically active and can citrullinate eukaryotic proteins, suggesting that the PADI HGT event introduced a new catalytic capability into the regulatory repertoire of animals. This study reveals the unusual evolution of a pleiotropic protein modification with clear relevance in human physiology and disease.

Extracellular Vesicle Signatures and Post-Translational Protein Deimination in Purple Sea Urchin (Strongylocentrotus purpuratus) Coelomic Fluid—Novel Insights into Echinodermata Biology

“…The lack of PAD orthologs in Echinoderms indicates that the transfer occurred after the major radiation events within the Deuterostoma and could explain the uniqueness of PADs in the chordate lineage. Furthermore, it has been shown that cyanobacteria PAD can actively citrullinate/deiminate mammalian proteins in a calcium-dependent manner [ 150 ], and this is in a similar vein as our suggestion here, based on the findings of our current study, that sea urchin proteins may be deiminated by cyanobacteria, or possibly other microbiota, PAD/ADI. The modulation of sea urchin immunity, metabolism, and gene regulation via deimination by PAD/ADI of microbiota could point to novel mechanisms in the regulation of key pathways in echinoderm biology.…”

“…Recent studies indicate the emergence of PADs within the chordates via horizontal gene transfer from cyanobacteria [ 150 ]. The lack of PAD orthologs in Echinoderms indicates that the transfer occurred after the major radiation events within the Deuterostoma and could explain the uniqueness of PADs in the chordate lineage.…”