Cyclic di-nucleotide signaling enters the eukaryote domain

Abstract

Cyclic (c-di-GMP) is the prevalent intracellular signaling intermediate in bacteria. It triggers a spectrum of responses that cause bacteria to shift from a swarming motile phase to sessile biofilm formation. However, additional functions for c-di-GMP and roles for related molecules, such as c-di-AMP and c-AMP-GMP continue to be uncovered. The first usage of cyclic-di-nucleotide (c-di-NMP) signaling in the eukaryote domain emerged only recently. In dictyostelid social amoebas, c-di-GMP is a secreted signal that induces motile amoebas to differentiate into sessile stalk cells. In humans, c-di-NMPs, which are either produced endogenously in response to foreign DNA or by invading bacterial pathogens, trigger the innate immune system by activating the expression of interferon genes. STING, the human c-di-NMP receptor, is conserved throughout metazoa and their closest unicellular relatives, suggesting protist origins for human c-di-NMP signaling. Compared to the limited number of conserved protein domains that detect the second messengers cAMP and cGMP, the domains that detect the c-di-NMPs are surprisingly varied.

Molecular evolutionary and structural analysis of the cytosolic DNA sensor cGAS and STING

“…The critical link is cGAMP which can activate STING to launch the type I IFN induction and also trigger negative-feedback control of STING activity (17,28,71). Therefore, contrary to the conclusion of Schaap that cGAS and STING did not evolve together (77), we speculate that cGAS has co-evolved with STING during the evolution of metazoans. Given that the critical functional zinc-ribbon domain and the most amino acid residues important for DNA binding in human cGAS are not conserved in early cGAS homologs, and even the CTT domain essential for STING activation and degradation through the ULK1-induced phosphorylation site S366, is also not conserved in early STING homologs, cGAS-STING may possibly play other roles in early metazoans rather than activating an innate immunity response to cytosolic DNA.…”

“…2′3′-cGAMP then activates STING, which further stimulates the downstream signaling pathway that leads to type I IFN production (17–18,28). The evolution of cGAS and STING was studied in two recent reviews (77,78). Schaap screened representative genomes of the major metazoan phyla and the choanoflagellate M. brevicollis using a modified best bi-directional BLASTP search, and found that STING homologs are distributed in all major animal phyla, except for porifera, and M. brevicollis .…”

UV Light Potentiates STING (Stimulator of Interferon Genes)-dependent Innate Immune Signaling through Deregulation of ULK1 (Unc51-like Kinase 1)

“…Other pathogen-derived cyclic dinucleotides, including 3Ј,3Ј-cGAMP and c-di-GMP, are released into the cytosol of mammalian cells upon infection with specific microbes and have been shown to bind and stimulate STING (16,18,19,46). As shown in Fig.…”

RNA-Based Fluorescent Biosensors for Live Cell Imaging of Second Messenger Cyclic di-AMP

“…The latter result provides the first experimental evidence that cyclic dinucleotide signaling extends to Archaea, in addition to bacteria and eukaryotes. 1,13 …”