Here are several kinds of cytosolic sensors in most cells that detect varieties of nucleic acids that shouldn't be there. Besides the cell's own single-stranded (ss), positive-sense (+) mRNA, the presence other cytosolic nucleic acids (like double or single strands of DNA or RNA of different senses) means that either pathogen infection, leakage of mtDNA from damaged mitochondria, or total nuclear breakdown has occurred. In any event, these are all ominous events that need to be addressed quickly before the cell is forced to roll out some kind of autodestruct plan.

The way cGAS-STING works is that upon DNA recognition, cGAS (Cyclic GMP-AMP synthase) dimerizes and stimulates formation of cyclic-GMP-AMP (cGAMP). This construct then binds and activates STING. In turn, STING phosphorylates the transcription factor IRF3 via TBK1, which then enters the nucleus to promote transcription inflammatory interferons like IFN-β. I asked Samuel why Nature has universally decided to synthesize cyclic dinucleotides as the definitive response to cytosolic nucleic acids. Specifically, whether the nucleic acids were being broken down to individual dNTPs (deoxynucleotides), converted into NTPs, and then used as the substrates for signaling cGAMP; or whether there would likely be plenty of purine NTP substrates already available in the cell. Although this question hasn't been addressed, at least to his knowledge, there may be some similarities with the common generation of cyclic nucletides in extracellular and even mitochondrial G-protein signal transduction.

Regards

John
Editorial Assistant
Immunogenetics Open Access