TNF[alpha]-induced metabolic reprogramming drives an intrinsic anti-viral state

• Published in: PLoS pathogens 2022-07, Vol.18 (7), p.e1010722
• Main Authors: Ciesla, Jessica, Moreno, Isreal, Munger, Joshua
• Format: Article
• Language: English
• Subjects: Development and progression; Genetic aspects; Immune response; Metabolic regulation; Physiological aspects; Tumor necrosis factor; Viral proteins; Virus diseases; Virus research
• ISSN: 1553-7366; 1553-7374
• DOI: 10.1371/journal.ppat.1010722

Cytokines induce an anti-viral state, yet many of the functional determinants responsible for limiting viral infection are poorly understood. Here, we find that TNF[alpha] induces significant metabolic remodeling that is critical for its anti-viral activity. Our data demonstrate that TNF[alpha] activates glycolysis through the induction of hexokinase 2 (HK2), the isoform predominantly expressed in muscle. Further, we show that glycolysis is broadly important for TNF[alpha]-mediated anti-viral defense, as its inhibition attenuates TNF[alpha]'s ability to limit the replication of evolutionarily divergent viruses. TNF[alpha] was also found to modulate the metabolism of UDP-sugars, which are essential precursor substrates for glycosylation. Our data indicate that TNF[alpha] increases the concentration of UDP-glucose, as well as the glucose-derived labeling of UDP-glucose and UDP-N-acetyl-glucosamine in a glycolytically-dependent manner. Glycolysis was also necessary for the TNF[alpha]-mediated accumulation of several glycosylated anti-viral proteins. Consistent with the importance of glucose-driven glycosylation, glycosyl-transferase inhibition attenuated TNF[alpha]'s ability to promote the anti-viral cell state. Collectively, our data indicate that cytokine-mediated metabolic remodeling is an essential component of the anti-viral response.