Two sensing arms, one output
Cytosolic RNA is detected by RIG-I and MDA5, which signal through the mitochondrial adaptor MAVS. Cytosolic DNA is detected by cGAS, which synthesizes cGAMP; cGAMP activates STING at the endoplasmic reticulum. Both arms converge on TBK1 and IRF3, which transcribe interferon-beta. The secreted interferon then engages its receptor and activates JAK1 and TYK2, which phosphorylate STAT1 and STAT2. The STAT1-STAT2-IRF9 complex transcribes hundreds of interferon-stimulated genes. Because the two sensing arms share the TBK1-IRF3 output, a single viral protein that blocks TBK1 can silence both RNA and DNA sensing at once.
Where viral proteins cut the pathway
- Shielding or degrading the viral RNA or DNA so no ligand is available to the sensor.
- Binding RIG-I, MDA5, MAVS, cGAS, or STING to prevent downstream signaling.
- Inhibiting TBK1 or IRF3 phosphorylation so interferon-beta is never transcribed.
- Binding STAT1 or STAT2, or inducing their degradation, so the cell cannot respond to interferon made by itself or by neighbors.
Upstream block versus downstream block
Blocking interferon production
- Reduces the initial interferon burst from the infected cell
- Neighboring cells may still sense infection and produce interferon
- Leaves the infected cell able to respond to interferon made elsewhere
Blocking interferon signaling
- The infected cell becomes deaf to interferon from any source
- Disables the paracrine amplification loop that recruits antiviral state in surrounding tissue
- Larger effect on the tissue-level response than blocking production alone
Blocking interferon signaling benefits a virus more than blocking production alone, because it removes both the cell's own antiviral response and its ability to be warned by neighboring cells. This is why STAT antagonists are among the most potent innate-evasion proteins and why their loss usually attenuates a virus.