Question

 

By way of comparison, detail the STING-dependent pathways using the mammalian DNA sensors DAI (DNA-activator of interferon), DDX41, and IFI16. What are the key common players in this pathway and what is the ultimate transcription factor involved in each?

Answer 1

STING acts as an adaptor protein in the dsDNA sensing pathway But it is not activated directly by DNA molecules. Actually, STING responds to DNA sensing proteins and molecules which are called cyclic dinucleotides (CDNs). These are derived from infectious agents exogenously or are produced by the mammalian dsDNA sensor cGAS (cyclic GMP-AMP synthase). This is universally expressed STING-activating DNA sensors. It is capable of catalysing a unique form of CDN endogenously during DNA recognition. This molecule is comprised of one 3′-5′ phosphodiester bond and a non-canonical 2′-5′ linkage between adenosine and guanosine, hence, it is named as 2′-3′ cGAMP. It has been found that the change of phosphodiester linkage in 2′-3′ cGAMP results in a higher binding affinity to STING and this leads to an augmented type I interferon response.

Fig. 1 STING activation pathways.

The Cytoplasmic DNA, released from DNA viruses or reverse transcribed from the RNA viral genome induce direct interaction between STING and DNA sensors such as DDX41, IFI16, and DAI. STING mediates antiviral responses with in the DNA sensors including DNA-dependent activator of IFN-regulatory factor (DAI), IFNγ-inducible protein 16 (IFI16), DEAD-Box Helicase 41 (DDX41) and components of the RNA-sensing pathways as shown in figure 1. The DNA sensor DAI is the first identified activator for STING. Its expression is highly cell-type and tissue-specific.