Interferon-stimulated gene products as regulators of central carbon metabolism

In response to viral infections, the innate immune system rapidly activates expression of several interferon-stimulated genes (ISGs), whose protein and metabolic products are believed to directly interfere with the viral life cycle. Here, we argue that biochemical reactions performed by two specific protein products of ISGs modulate central carbon metabolism to support a broad-spectrum antiviral response. We demonstrate that the metabolites generated by metalloenzymes nitric oxide synthase and the radical S-adenosylmethionine (SAM) enzyme RSAD2 inhibit the activity of the housekeeping and glycolytic enzyme glyceraldehyde 3-phosphate dehydrogenase (GAPDH). We discuss that this inhibition is likely to stimulate a range of metabolic and signalling processes to support a broad-spectrum immune response. Based on these analyses, we propose that inhibiting GAPDH in individuals with deteriorated cellular innate immune response like elderly might help in treating viral diseases such as COVID-19.