Limiting Cholesterol Biosynthetic Flux Spontaneously Engages Type I IFN Signaling

• Published in: Cell Vol. 163; no. 7; pp. 1716 - 1729
• Main Authors: York, Autumn G., Williams, Kevin J., Argus, Joseph P., Zhou, Quan D., Brar, Gurpreet, Vergnes, Laurent, Gray, Elizabeth E., Zhen, Anjie, Wu, Nicholas C., Yamada, Douglas H., Cunningham, Cameron R., Tarling, Elizabeth J., Wilks, Moses Q., Casero, David, Gray, David H., Yu, Amy K., Wang, Eric S., Brooks, David G., Sun, Ren, Kitchen, Scott G., Wu, Ting-Ting, Reue, Karen, Stetson, Daniel B., Bensinger, Steven J.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 17.12.2015
• Subjects: Animals; biochemical pathways; biosynthesis; Cell Line, Tumor; cholesterol; Cholesterol - metabolism; Humans; Immunity, Innate; innate immunity; Interferon beta-1b; Interferon-gamma - metabolism; interferons; isotopes; long chain fatty acids; macrophages; Membrane Proteins - metabolism; Mevalonic Acid - metabolism; Mice; Mice, Inbred C57BL; Signal Transduction; Sterol Regulatory Element Binding Protein 1 - metabolism; Sterol Regulatory Element Binding Protein 2 - metabolism
• ISSN: 0092-8674; 1097-4172; 1097-4172
• DOI: 10.1016/j.cell.2015.11.045

Cellular lipid requirements are achieved through a combination of biosynthesis and import programs. Using isotope tracer analysis, we show that type I interferon (IFN) signaling shifts the balance of these programs by decreasing synthesis and increasing import of cholesterol and long chain fatty acids. Genetically enforcing this metabolic shift in macrophages is sufficient to render mice resistant to viral challenge, demonstrating the importance of reprogramming the balance of these two metabolic pathways in vivo. Unexpectedly, mechanistic studies reveal that limiting flux through the cholesterol biosynthetic pathway spontaneously engages a type I IFN response in a STING-dependent manner. The upregulation of type I IFNs was traced to a decrease in the pool size of synthesized cholesterol and could be inhibited by replenishing cells with free cholesterol. Taken together, these studies delineate a metabolic-inflammatory circuit that links perturbations in cholesterol biosynthesis with activation of innate immunity. [Display omitted] •Identification of a cholesterol metabolism-type I interferon (IFN) inflammatory circuit•Type I interferon reprograms cholesterol homeostasis•Perturbing cholesterol synthesis engages type I IFN signaling•STING/TBK1 links cholesterol metabolism with type I interferon pathway Cholesterol metabolism and type I interferon response are co-regulated in macrophages, creating an immuno-metabolic circuit that allows innate immune cells to coordinate metabolism changes with immune activation required for antiviral responses.