The STING ligand 2′3′-cGAMP induces an NF-κB-dependent anti-bacterial innate immune response in the starlet sea anemone Nematostella vectensis

In mammals, the cGAS-cGAMP-STING pathway is crucial for sensing viral infection and initiating an anti-viral type I interferon response. cGAS and STING are highly conserved genes that originated in bacteria and are present in most animals. By contrast, interferons only emerged in vertebrates; thus, the function of STING in invertebrates is unclear. Here, we use the STING ligand 2′3′-cGAMP to activate immune responses in a model cnidarian invertebrate, the starlet sea anemone Nematostella vectensis. Using RNA-Seq, we found that 2′3′-cGAMP induces robust transcription of both anti-viral and anti-bacterial genes, including the conserved transcription factor NF-κB. Knockdown experiments identified a role for NF-κB in specifically inducing anti-bacterial genes downstream of 2′3′-cGAMP, and some of these genes were also found to be induced during Pseudomonas aeruginosa infection. Furthermore, we characterized the protein product of one of the putative anti-bacterial genes, the N. vectensis homolog of Dae4, and found that it has conserved anti-bacterial activity. This work describes an unexpected role of a cGAMP sensing pathway in anti-bacterial immunity and suggests that a broad transcriptional response is an evolutionarily ancestral output of 2′3′-cGAMP signaling in animals.