Cytosolic d-type CpG-oligonucleotides induce a type I interferon response by activating the cGAS-STING signaling pathway.
Christian BodeJens Martin PothMario FoxSusanne SchulzDennis M KlinmanEicke LatzFolkert SteinhagenPublished in: European journal of immunology (2021)
Cytosolic DNA receptor cyclic GMP-AMP (cGAMP) synthase (cGAS) has been shown to be critically involved in the detection of cytosolic, self- and non-self-DNA, initiating a type I IFN response through the adaptor protein Stimulator of Interferon Genes (STING) and interferon regulatory factor 3 (IRF3). Current studies propose that canonical binding of dsDNA by cGAS depends on DNA length, but not on base sequence. In contrast, activation of TLR9 is sequence dependent. It requires unmethylated CpG dinucleotides in microbial DNA, which is mimicked by synthetic oligodeoxynucleotides (ODN). Here, we provide evidence that d-type ODN (D-ODN), but not K-type ODN (K-ODN), bind to human cGAS and activate downstream signaling. Transfection of D-ODN into a TLR9-deficient, human monocytic cell line (THP-1) induced phosphorylation of IRF3 and secretion of IFN. This response was absent in cells with CRISPR/Cas9-mediated cGAS- or STING-deficiency. Utilizing a protein pulldown approach, we further demonstrate direct binding of D-ODN to cGAS. Induction of a type I IFN response by D-ODN was confirmed in human primary monocytes and monocyte-derived macrophages. These results are relevant to our understanding of self-nonself-discrimination by cGAS and to the pharmacologic effects of ODN, which currently are investigated in clinical studies.
Keyphrases
- dendritic cells
- endothelial cells
- immune response
- circulating tumor
- signaling pathway
- crispr cas
- cell free
- single molecule
- induced apoptosis
- induced pluripotent stem cells
- high glucose
- inflammatory response
- nucleic acid
- binding protein
- magnetic resonance
- magnetic resonance imaging
- dna methylation
- toll like receptor
- genome editing
- computed tomography
- microbial community
- amino acid
- cystic fibrosis
- staphylococcus aureus
- gene expression
- pi k akt
- genome wide
- small molecule
- mass spectrometry
- biofilm formation
- high resolution
- cell proliferation
- drug induced
- label free