Editors' ChoiceMetabolism

Reprogramming lipid metabolism to boost antiviral responses

See allHide authors and affiliations

Science Signaling  05 Jan 2016:
Vol. 9, Issue 409, pp. ec3
DOI: 10.1126/scisignal.aaf1790

Antiviral inflammatory signaling triggered by Toll-like receptors 3 and 4 (TLR3/4) and type I interferon (IFN) decreases de novo cholesterol biosynthesis yet paradoxically increases cholesterol uptake. York et al. found that this change in lipid metabolism could itself trigger type I IFN signaling. Exposure of bone marrow–derived macrophages to IFN-β or poly:IC (a TLR3 ligand) or infection of these cells with murine gammaherpesvirus-68 (MHV-68) suppressed the synthesis of saturated and unsaturated long-chain fatty acids and cholesterol while increasing the import of fatty acids and cholesterol. Sterol regulatory element–binding protein 1 and 2 (SREBP1 and SREBP2) promote the expression of genes encoding enzymes involved in cholesterol and fatty acid biosynthesis and require SREBP cleavage–activating protein (SCAP) for their activity. Mice with a macrophage-specific deletion of Scap were resistant to MHV-68 infection. Macrophages from these mice showed changes in lipid homeostasis that were similar to those induced by IFN-β, had increased basal expression of IFN-stimulated genes, released more IFN basally, and exhibited an increase in some inflammatory responses. In primary human peripheral blood mononuclear cells or THP1 cells, knockdown of SREBP2 increased the basal expression of IFN-stimulated genes and promoted resistance to viral infection. Cholesterol supplementation reduced the expression of IFN-stimulated genes in THP1 cells with SBREBP2 knockdown and increased viral load in Scap–/– macrophages. Upon binding to cytosolic double-stranded DNA from viruses, the enzyme cyclic GMP–AMP synthase (cGAS) generates the cyclic dinucleotide cGAMP, which activates STING (stimulator of interferon genes). Activation of STING causes TANK-binding kinase 1 (TBK1) to phosphorylate and activate interferon regulatory factor 3 (IRF3), which mediates the transcription of IFN-encoding genes. The expression of IFN-stimulated genes in SREBP2-deficient mouse embryonic fibroblasts (MEFs) or macrophages required the expression of Ifnb, which depended on IRF3, TBK1, STING, and the generation of STING ligands by cGAS. In Scap–/– macrophages, TBK1 phosphorylation was decreased by cholesterol supplementation and increased by application of an exogenous STING ligand. Thus, the shift in lipid homeostasis triggered by IFN that is produced because of viral infection further drives and reinforces antiviral responses (see O’Neill).

A. G. York, K. J. Williams, J. P. Argus, Q. D. Zhou, G. Brar, L. Vergnes, E. E. Gray, A. Zhen, N. C. Wu, D. H. Yamada, C. R. Cunningham, E. J. Tarling, M. Q. Wilks, D. Casero, D. H. Gray, A. K. Yu, E. S. Wang, D. G. Brooks, R. Sun, S. G. Kitchen, T.-T. Wu, K. Reue, D. B. Stetson, S. J. Bensinger, Limiting cholesterol biosynthetic flux spontaneously engages type I IFN signaling. Cell 163, 1716–1729 (2015). [PubMed]

L. A. J. O’Neill, How low cholesterol is good for anti-viral immunity. Cell 163, 1572–1574 (2015). [PubMed]

Stay Connected to Science Signaling