STING AQ variant (human, recombinant)

STING AQ variant (human recombinant) contains amino acids 138-379 of the wild-type STING variant (R232) with an alanine substituted for glycine at position 230 and a glutamine substituted for arginine at position 293. Stimulator of interferon genes (STING) is a component of the innate immune response that binds to cyclic dinucleotides, which are bacterial second messengers.¹ Recognition of cyclic-di-GMP (c-di-GMP), c-di-AMP, or c-GMP-AMP leads to activation of NF-κB and transcription of immunomodulatory genes, including type I interferons (IFN).^2,3,4 The R232 variant of STING is the most common variant in the human population, found at a frequency of 57.9% in the 1000 Genome Project.⁵ The SNP variant H232 is found at a 13.7% frequency. The G230A, R293Q double mutation occurs in 5.2% of the human population and when expressed in HEK293T cells, this mutation reduces the IFN response to bacterial ligands by 30-40% compared to wild-type STING. Whereas the R293Q substitution alone is severely defective in response to bacterial cyclic dinucleotides, the G230A substitution is thought to help maintain some ability of this variant to respond to bacterial cyclic dinucleotides. Based on crystal structure of STING, the G230A mutation alters the conformation of the lid region that clamps onto the c-di-GMP, however, the R293 residue does not directly bind to c-di-GMP.⁵ The R293Q mutation may instead disrupt STING activity indirectly by altering the function of a nearby cysteine residue required for IFN-β expression.⁶

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1. Burdette, D.L., Monroe, K.M., Sotelo-Troha, K., et al. STING is a direct innate immune sensor of cyclic-di-GMP. Nature 478(7370), 515-518 (2011).

2. Sun, L., Wu, J., Du, F., et al. Cyclic GMP-AMP synthase is a cytosolic DNA sensor that activates the type I interferon pathway. Science 339(6121), 786-791 (2013).

3. Wu, J., Sun, L., Chen, X., et al. Cyclic GMP-AMP is an endogenous second messenger in innate immune signaling by cytosolic DNA. Science 339(6121), 826-830 (2013).

4. Konno, H., Konno, K., and Barber, G.N. Cyclic dinucleotides trigger ULK1 (ATG1) phosphorylation of STING to prevent sustained innate immune signaling. Cell 155(3), 688-698 (2013).

5. Yi, G., Brendel, V.P., Shu, C., et al. Single nucleotide polymorphisms of human STING can affect innate immune response to cyclic dinucleotides. PLoS One 8(10), e77846 (2013).

6. Jin, L., Xu, L.-G., Yang, I.V., et al. Identification and characterization of a loss-of-function human MPYS variant. Genes Immun. 12(4), 263-269 (2011).