STING H232 variant (human, recombinant)

Stimulator of interferon genes (STING) is a component of the innate immune response that binds to cyclic dinucleotides, which are bacterial second messengers, leading to activation of NF-κB and transcription of immunomodulatory genes, including type I interferon (IFN).^1,2,3,4 The H232 variant of STING is found at a 13.7% frequency in the 1000 Genome Project.⁵ The SNP variant R232 (Item No. 22816) is the most common variant in the human population, found at a frequency of 57.9%. Various mutations in STING either reduce or increase its activity. Gain-of-function mutations in STING, including R284M (Item No. 23594) and V155M, lead to constitutive activation and enhancement of the type I IFN response.^5,6 The V155M mutation is associated with a systemic inflammatory condition, including pulmonary fibrosis and autoimmune factors.⁶ Mutations that reduce STING activity include K224R (Item No. 23593), which reduces ubiquitination of STING thereby disrupting its localization within the cell, and the double mutation G230A, R293Q (Item No. 23592), which reduces the IFN response.^5,7 A T596A mutation present in the mouse strain Goldenticket leads to a complete loss of STING protein and lack of a type I IFN response to infection by Listeria.⁸

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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. Jeremiah, N., Neven, B., Gentili, M., et al. Inherited STING-activating mutation underlies a familial inflammatory syndrome with lupus-like manifestations. J. Clin. Invest. 124(12), 5516-5520 (2014).

7. Ni, G., Konno, H., and Barber, G.N. Ubiquitination of STING at lysine 224 controls IRF3 activation. Sci. Immunol. 2(11), eaah7119 (2017).

8. Sauer, J.D., Sotelo-Troha, K., von Moltke, J., et al. The N-ethyl-N-nitrosourea-induced Goldenticket mouse mutant reveals an essential function of Sting in the in vivo interferon response to Listeria monocytogenes and cyclic dinucleotides. Infect. Immun. 79(2), 688-694 (2011).