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 Kitchen; Ting-Ting Wu; Karen Reue; Daniel B Stetson; Steven J Bensinger

doi:10.1016/j.cell.2015.11.045

Limiting Cholesterol Biosynthetic Flux Spontaneously Engages Type I IFN Signaling

Cell. 2015 Dec 17;163(7):1716-29. doi: 10.1016/j.cell.2015.11.045. Epub 2015 Dec 10.

Authors

Autumn G York¹, Kevin J Williams², Joseph P Argus¹, Quan D Zhou¹, Gurpreet Brar¹, Laurent Vergnes³, Elizabeth E Gray⁴, Anjie Zhen⁵, Nicholas C Wu⁶, Douglas H Yamada⁷, Cameron R Cunningham², Elizabeth J Tarling⁸, Moses Q Wilks⁹, David Casero¹⁰, David H Gray¹¹, Amy K Yu¹, Eric S Wang¹, David G Brooks¹², Ren Sun¹, Scott G Kitchen⁵, Ting-Ting Wu¹, Karen Reue¹³, Daniel B Stetson⁴, Steven J Bensinger¹⁴

Affiliations

¹ Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
² Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA.
³ Department of Human Genetics, University of California, Los Angeles, David Geffen School of Medicine, Los Angeles, CA 90095, USA.
⁴ Department of Immunology, University of Washington, 750 Republican Street, Box 358059, Seattle, WA 98109, USA.
⁵ Division of Hematology/Oncology, University of California, Los Angeles, David Geffen School of Medicine, Los Angeles, CA 90095, USA; UCLA AIDS Institute and the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, Los Angeles, CA 90095, USA.
⁶ Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA.
⁷ Immuno-Oncology Discovery Research; Janssen Research & Development, LLC, Spring House, PA 19477, USA.
⁸ Division of Cardiology, University of California, Los Angeles, David Geffen School of Medicine, Los Angeles, CA 90095, USA; Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA.
⁹ Center for Advanced Medical Imaging Sciences, Department of Radiology, Massachusetts General Hospital, Boston, MA 02114, USA.
¹⁰ Department of Pathology and Laboratory Medicine, University of California, Los Angeles, David Geffen School of Medicine, Los Angeles, CA 90095, USA.
¹¹ Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA; Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA.
¹² Princess Margaret Cancer Center, Immune Therapy Program, University Health Network, Toronto, ON M5G 2M9, Canada; Department of Immunology, University of Toronto, Toronto, ON M5S 1A8, Canada.
¹³ Department of Human Genetics, University of California, Los Angeles, David Geffen School of Medicine, Los Angeles, CA 90095, USA; Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA.
¹⁴ Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Pathology and Laboratory Medicine, University of California, Los Angeles, David Geffen School of Medicine, Los Angeles, CA 90095, USA. Electronic address: sbensinger@mednet.ucla.edu.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cell Line, Tumor
Cholesterol / metabolism*
Humans
Immunity, Innate*
Interferon beta-1b
Interferon-gamma / metabolism*
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

Substances

Membrane Proteins
Srebf1 protein, mouse
Srebf2 protein, mouse
Sterol Regulatory Element Binding Protein 1
Sterol Regulatory Element Binding Protein 2
Interferon beta-1b
Interferon-gamma
Cholesterol
Mevalonic Acid

Associated data

GEO/GSE73942

Abstract

Publication types

MeSH terms

Substances

Associated data

Grants and funding