Limiting Cholesterol Biosynthetic Flux Spontaneously Engages Type i IFN Signaling

Autumn G. York, Kevin J. Williams, Joseph P. Argus, Quan D. Zhou, Gurpreet Brar, Laurent Vergnes, Elizabeth E. Gray, Anjie Zhen, Nicholas C. Wu, Douglas H. Yamada, Cameron R. Cunningham, Elizabeth J. Tarling, Moses Q. Wilks, David Casero, David H. Gray, Amy K. Yu, Eric S. Wang, David G. Brooks, Ren Sun, Scott G. KitchenTing Ting Wu, Karen Reue, Daniel B. Stetson, Steven J. Bensinger

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1716-1729
Number of pages14
JournalCell
Volume163
Issue number7
DOIs
StatePublished - Dec 17 2015
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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