The Prokaryotic Roots of Eukaryotic Immune Systems

Over the past two decades, studies have revealed profound evolutionary connections between prokaryotic and eukaryotic immune systems, challenging the notion of their unrelatedness. Immune systems across the tree of life share an operational framework, shaping their biochemical logic and evolutionary trajectories. The diversification of immune genes in the prokaryotic superkingdoms, followed by lateral transfer to eukaryotes, was central to the emergence of innate immunity in the latter. These include protein domains related to nucleotide second messenger–dependent systems, NAD+/nucleotide degradation, and P-loop NTPase domains of the STAND and GTPase clades playing pivotal roles in eukaryotic immunity and inflammation. Moreover, several domains orchestrating programmed cell death, ultimately of prokaryotic provenance, suggest an intimate link between immunity and the emergence of multicellularity in eukaryotes such as animals. While eukaryotes directly adopted some proteins from bacterial immune systems, they repurposed others for new immune functions from bacterial interorganismal conflict systems. These emerging immune components hold substantial biotechnological potential.