Eukaryotic antiviral immune proteins arose via convergence, horizontal transfer, and ancient inheritance

Abstract

Animals use a variety of cell-autonomous innate immune proteins to detect viral infections and prevent replication. Recent studies have discovered that a subset of mammalian antiviral proteins have homology to anti-phage defense proteins in bacteria, implying that there are aspects of innate immunity that are shared across the Tree of Life. While the majority of these studies have focused on characterizing the diversity and biochemical functions of the bacterial proteins, the evolutionary relationships between animal and bacterial proteins are less clear. This ambiguity is partly due to the long evolutionary distances separating animal and bacterial proteins, which obscures their relationships. Here, we tackle this problem for three innate immune families (CD-NTases [including cGAS], STINGs, and Viperins) by deeply sampling protein diversity across eukaryotes. We find that Viperins are truly ancient immune proteins, likely inherited since the last eukaryotic common ancestor and possibly longer. In contrast, we find other immune proteins that arose via at least five independent events of horizontal gene transfer (HGT) from bacteria. Two of these events allowed algae to acquire new bacterial viperins, while three more HGT events gave rise to distinct superfamilies of eukaryotic CD-NTases: the OAS superfamily, which is widespread across eukaryotes; the Mab21 superfamily (containing cGAS) which has diversified via a series of animal-specific duplications, and a previously undefined eSMODS superfamily, which more closely resembles bacterial CD-NTases. Finally, we found that cGAS and STING proteins have substantially different histories, with STINGs arising via convergent domain shuffling in bacteria and eukaryotes. Overall, our findings paint a picture of eukaryotic innate immunity as highly dynamic, where eukaryotes build upon their ancient antiviral repertoires through the reuse of protein domains and by repeatedly sampling a rich reservoir of bacterial anti-phage genes.

Viperin immunity evolved across the tree of life through serial innovations on a conserved scaffold

“…For instance, cGLRs, recently uncovered eukaryotic homologs of the human and prokaryotic immune gene cGAS 38,39 , also seem to show a more specific biochemistry in eukaryotes in the signal molecules produced as well as additional fused domains. However, contrary to viperins, cGLRs appear to have emerged from a relatively recent event of horizontal gene transfer 40 and are thus restricted to a specific clade of eukaryotes. Whether similar evolutionary histories and dynamics are shared by other immune systems present in both prokaryotes and eukaryotes remains a topic that requires further elucidation.…”

Recurrent Viral Capture of Cellular Phosphodiesterases that Antagonize OAS-RNase L

“…In contrast, we characterize an example of gene transfer shaping virus interactions with host immunity, with potential implications for host-range and virulence. A recent report proposing bacterial origins for eukaryotic OAS genes, suggests that both sides of the interface between viral PDE and OAS-RNase L arose via horizontal gene transfer (20). Understanding how HGT has influenced virus-innate immune interfaces benefits from a better understanding of the emergence of newly captured viral genes and their subsequent evolution.…”