GAPDH is normally thought of as being a glycolytic enzyme. However, it has another role that of binding RNA and being a modulator of gene expression which helps explain why it has specific inhibitory roles against coronaviruses. The list below shows how GAPDH likely plays an important role in the pathology of coronavirus infections:
1. Downregulation of GAPDH causes an upregulation of viral transcription of TGEV, a coronavirus belonging to the alpha subfamily of this virus.
2. siRNA directed against GAPDH in macrophages causes a 66% decrease in the amount of secreted interferon gamma (IFNg, an important cytokine against viruses in general). This result was confirmed by other studies that used GAPDH-specific inhibitors. It should also be noted that GAPDH also modulates expression of TNF alpha, an important inflammatory cytokine.
3. GAPDH is a negative transcriptional regulator of AT1R, which has been known to bind to ACE2, the host receptor to which the SARS coronaviruses attach. It’s worth mentioning that AT1R has also been linked to inflammation and fibrosis.
4. The GAIT complex is a quaternary protein structure formed around 24 hours after IFNg secretion that bind to the mRNA of IFNg-responsive genes to terminate translation. This is important for the resolution of an inflammatory response which requires GAPDH as the last protein to assemble.
Furthermore, there is a strong transduction link between interferon gamma and nitric oxide production whereby this cytokine (either by itself or in combination with other cytokines) stimulates inducible nitric oxide synthetase (iNOS). Studies have shown that iNOS levels then is able to upregulate GAPDH levels thereby completing a feedback loop which is summarized in the figure.
Since the current SAR-CoV-2 (as well as the previous SAR-CoV) strain have been shown to decrease GAPDH levels upon infection, it would imply downstream effects on both interferon gamma and nitric oxide, both of which are known coronavirus inhibitors.
By understanding the interrelationship of these important anti-viral molecules, perhaps it will help us in understanding the human host cell’s defenses against coronaviruses.
Inhibitors of Coronaviruses
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