Interferon‐stimulated gene products as regulators of central carbon metabolism

• Published in: The FEBS journal Vol. 288; no. 12; pp. 3715 - 3726
• Main Authors: Ebrahimi, Kourosh H., Gilbert‐Jaramillo, Javier, James, William S., McCullagh, James S.O.
• Format: Journal Article
• Language: English
• Published: Oxford Blackwell Publishing Ltd 01.06.2021; John Wiley and Sons Inc
• Subjects: Adenosylmethionine; Carbon; COVID-19; Enzymes; GAPDH; Glyceraldehyde; Glyceraldehyde-3-phosphate dehydrogenase; Glycolysis; Immune response; Immune system; immunometabolism; Innate immunity; Interferon; ISG; Life cycles; Metabolism; Metabolites; Nitric oxide; Nitric-oxide synthase; Proteins; Viewpoint; viperin; Viral diseases; viruses
• ISSN: 1742-464X; 1742-4658
• DOI: 10.1111/febs.15625

ISG products are believed to directly block viral replication. We propose an alternative mechanism based on emerging evidence. We discuss that the metabolic products of two ISG proteins, namely RSAD2 and NOS, inhibit activity of GAPDH to regulate central carbon metabolism and support a broad‐spectrum antiviral immune response via at least four mechanisms: eicosanoids storm, antigen cross‐presentation via MHC‐I, modulating NFAT and NF‐κB pathways, and S‐nitrosylation of viral proteins. 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.