The cyclic dinucleotide 2’3’-cGAMP induces a broad anti-bacterial and anti-viral response in the sea anemone Nematostella vectensis

Abstract

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.

STING mediates immune responses in the closest living relatives of animals

“…Here, we observed that STING is required for induction of the autophagy pathway in response to 2’3’ cGAMP in M. brevicollis , indicating that the role of STING in regulating autophagy predates animal origins. While exposure to 2’3’ cGAMP leads to NF-kB activation in the sea anemone N. vectensis ( Margolis, 2021 ) and in insects ( Cai et al, 2020 ; Martin et al, 2018 ; Goto et al, 2018 ; Hua et al, 2018 ), neither M. brevicollis nor S. macrocollata , the two choanoflagellate species with STING, possess a NF-kB homolog ( Richter et al, 2018 ). Nonetheless, 2’3’ cGAMP activates an extensive transcriptional response downstream of STING in M. brevicollis , although the specific signaling pathways remain to be identified.…”

STING mediates immune responses in the closest living relatives of animals

“…Here, we observed that STING is required for induction of the autophagy pathway in response to 2'3' cGAMP in M. brevicollis, indicating that the role of STING in regulating autophagy predates animal origins. While exposure to 2'3' cGAMP leads to NF-kB activation in the sea anemone N. vectensis 58 and in insects [59][60][61][62] , neither M. brevicollis nor S. macrocollata, the two choanoflagellate species with STING, possess a NF-kB homolog 3 . Nonetheless, 2'3' cGAMP activates an extensive transcriptional response downstream of STING in M. brevicollis, although the specific signaling pathways remain to be identified.…”