Viral trespassers leave traces of themselves as they overtake cells. The presence of hallmark viral molecules—called PAMPs, for pathogen-associated molecular patterns—allows innate immune system sensors to detect the trail of viral substances as effectively as Sherlock Holmes in miniature.
Some of these sensors, or pattern recognition receptors (PRRs), nose out viral DNA and RNA. When they detect viral nucleic acids they elicit type I interferon, cytokines, and/or chemokines; this in turn calls the cavalry to the rescue, ultimately bringing about an adaptive immune response for a search-and-destroy mission.
Identifying proteins that act as nucleic acid-responsive PRRs happened surprisingly recently. It was 2008 before STING was pinpointed as acting upstream of TANK binding kinase 1 (TBK1) and the transcriptional regulators of interferon (IRF3 and IRF7). Subsequent studies showed that STING is critical for the ability to detect cytosolic viral DNA. “STING-less” knockout mice were more susceptible to infection with herpes simplex 1 (HSV-1) virus. Interestingly, they were also more susceptible to RNA viruses such as vesicular stomatitis virus, through probably through a different and more indirect mechanism than is involved in responding to viral DNA.
The response to cytosolic DNA begins when a DNA sensor upstream of STING called cGAS, that binds DNA and catalyzes the production of cGAMP from ATP and GTP. cGAMP then serves as a second messenger, binding and activating STING for type I interferon production. During this process, STING dimerizes, moves to a perinuclear location, and begins activating downstream signaling pathways. Perinuclear localization doesn’t happen in response to viral RNA.
What makes the cGAS/STING pathway so intriguing? A single receptor that helps to combat a plethora of viral pathogens is compelling—but given the inevitable battle between pathogen and host, the situation quickly becomes complicated. Multiple viruses have evolved ways to counteract STING or cGAS. For example, ICP0 or ICP4 deletion mutants of HSV-1 cause STING to degrade. Hepatitis B polymerase inhibits STING-triggered IFN-beta promoter activation; either of the reverse transcriptase or the RNase H domains of HBV polymerase are sufficient for inhibition. (For more about RNase H involvement in STING function, stay tuned for the next blog post.)
RNA viruses have ways to counteract STING as well: the non-structural protein NS4B of yellow fever virus (YFV) can interact with STING, blocking STING and RIG-I-dependent signaling. Similarly, NS4B homologs from Dengue virus and hepatitis C virus also colocalize with STING, disrupting its interactions with other complex members. Human coronavirus takes an analogous strategy, preventing STING dimerization and STING-TBK1 interaction through a membrane-anchored PLP.