Abstract
The STING (stimulator of interferon genes) protein can bind cyclic dinucleotides to activate the production of type I interferons and inflammatory cytokines. The cyclic dinucleotides can be bacterial second messengers c-di-GMP and c-di-AMP, 3’5’-3’5’ cyclic GMP-AMP (3’3’ cGAMP) produced by Vibrio cholerae and metazoan second messenger 2’5’-3’5’ Cyclic GMP-AMP (2’3’ cGAMP). Analysis of single nucleotide polymorphism (SNP) data from the 1000 Genome Project revealed that R71H-G230A-R293Q (HAQ) occurs in 20.4%, R232H in 13.7%, G230A-R293Q (AQ) in 5.2%, and R293Q in 1.5% of human population. In the absence of exogenous ligands, the R232H, R293Q and AQ SNPs had only modest effect on the stimulation of IFN-β and NF-κB promoter activities in HEK293T cells, while HAQ had significantly lower intrinsic activity. The decrease was primarily due to the R71H substitution. The SNPs also affected the response to the cyclic dinucleotides. In the presence of c-di-GMP, the R232H variant partially decreased the ability to activate IFN-βsignaling, while it was defective for the response to c-di-AMP and 3’3’ cGAMP. The R293Q dramatically decreased the stimulatory response to all bacterial ligands. Surprisingly, the AQ and HAQ variants maintained partial abilities to activate the IFN-β signaling in the presence of ligands due primarily to the G230A substitution. Biochemical analysis revealed that the recombinant G230A protein could affect the conformation of the C-terminal domain of STING and the binding to c-di-GMP. Comparison of G230A structure with that of WT revealed that the conformation of the lid region that clamps onto the c-di-GMP was significantly altered. These results suggest that hSTING variation can affect innate immune signaling and that the common HAQ haplotype expresses a STING protein with reduced intrinsic signaling activity but retained the ability to response to bacterial cyclic dinucleotides.
Highlights
The innate immune system is the first line of defense against microbial pathogen infection, including viral and bacterial infection, and tissue damage
STING isoforms in human populations growing evidences suggest that the genetic variation of innate immune sensors could affect the susceptibility of human diseases [32,33], the linkage between single nucleotide polymorphisms in human STING and diseases remains to be established
We examined the haplotypes of 1,090 individuals whose genomes have been sequenced as part of the 1000 Genomes project [29]. 76 bi-allelic single nucleotide polymorphism (SNP) are observed in the 7,231-bp STING gene, including 7 in the 5’ untranslated regions (UTR), 26 in the coding sequence, 38 in introns, and 5 in the 3′ UTR, corresponding to rates per 1 kb of 6.64, 22.81, 8.83, and 6.82, respectively
Summary
The innate immune system is the first line of defense against microbial pathogen infection, including viral and bacterial infection, and tissue damage It is initiated by germ lineencoded pattern recognition receptors to detect ligands from the pathogen as well as from damage-associated molecular patterns [1]. It was reported that cyclic GMPAMP (cGAMP) could bind to STING and result in activation of IRF3 and β-interferon production [15,16] Both 3’5’-3’5’ cGAMP (to be designated 3’3’ cGAMP) produced by Vibrio cholera [17], and the metazoan secondary messenger cyclic [G(2’,5’)pA(3’5’)] (to be named 2’3’ cGAMP), could activate the innate immune response through STING pathway [18,19,20,21]. STING seems to play an important role in the autoimmune diseases by the inappropriate recognition of self DNA [22]
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