Innate immunity and bacterial conflict: the deep origins of cGAS-STING signaling and discovery of uncharacterized animal immunity pathways

Abstract

Abstract Just as animal innate immunity pits endogenous response pathways against invading extragenic threats, microbiomes are governed by myriad pathways mediating inter-genomic resource procurement, collectively known as ‘conflict systems.’ Leveraging the continually-increasing amount of genome data, we have probed such systems and in the process uncovered the evolutionary origins of core components of animal immunity. This includes the discovery that cyclic-nucleotide synthesizing enzymes like human cGAS and OAS1 and their receptors like STING were acquired from comparable conflict-triggered nucleotide signaling systems in bacteria. While our analyses point to previously-unknown diversity animal innate immunity, particularly in marine invertebrates, this diversity pales in contrast to bacterial pathways which contain a wealth of completely uncharacterized nucleotide synthetase enzymes, nucleotide receptors, and response effector domains. Further, studies from our group point to entirely-uncharacterized components of the animal innate immunity response that have also been acquired from bacterial conflict systems. These include the viral RNA-acting human Leng9 phosphoesterase and the human N4BP2L1 nucleotide kinase. These studies also uncover a connection between immunity-driven second messenger nucleotide generation and a previously-unrecognized receptor domain in the human apoptotic factor MAP3K5.