Nucleic acid sensing by STING induces an interferon-like antiviral response in a marine invertebrate

ABSTRACT The cytosolic detection of pathogen derived nucleic acids has evolved as an essential strategy for host innate immune defense in mammals. The stimulator of interferon genes (STING) functions as a crucial signaling adaptor, linking the cytosolic detection of DNA by cyclic GMP-AMP (cGAMP) synthase (cGAS) to the downstream Type I interferon (IFN) signaling axis. However, this process remains elusive in invertebrates. Herein, we demonstrated that a STING ortholog from a marine invertebrate (shrimp) Litopenaeus vannamei can directly sense DNA to activate an interferon-like antiviral response. Unlike STING homologs exclusively functioning as a sensor for cyclic dinucleotides (CDNs) in other eukaryotic organisms, shrimp STING can bind to double-stranded DNA (dsDNA) in addition to CDNs, including 2′3′-cGAMP. In vivo , shrimp STING can directly sense DNA nucleic acids from an infected virus, accelerate IRF dimerization, nuclear translocation and induce the expression of an interferon functional analog protein (Vago4), and finally establish an antiviral state. Surprisingly, the shrimp cGAS-like homolog is not involved in dsDNA-intrigued and STING-dependent IRF–Vago axis activation. Taken together, our results uncovered a novel dsDNA–STING–IKKε–IRF–Vago antiviral axis in an arthropod, and provided some novel insights into the functional origin of a DNA-sensing pathway in evolution.