title: Limiting Cholesterol Biosynthetic Flux Spontaneously Engages Type I IFN Signaling.
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.
authors.affiliation: Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Autumn G
authors.initials: AG
authors.lastname: York
authors.affiliation: Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Williams
authors.affiliation: Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Argus
authors.affiliation: Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Quan D
authors.initials: QD
authors.lastname: Zhou
authors.affiliation: Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Gurpreet
authors.initials: G
authors.lastname: Brar
authors.affiliation: Department of Human Genetics, University of California, Los Angeles, David Geffen School of Medicine, Los Angeles, CA 90095, USA.
authors.forename: Laurent
authors.initials: L
authors.lastname: Vergnes
authors.affiliation: Department of Immunology, University of Washington, 750 Republican Street, Box 358059, Seattle, WA 98109, USA.
authors.forename: Elizabeth E
authors.initials: EE
authors.lastname: Gray
authors.affiliation: 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.
authors.forename: Anjie
authors.initials: A
authors.lastname: Zhen
authors.affiliation: 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.
authors.forename: Nicholas C
authors.initials: NC
authors.lastname: Wu
authors.affiliation: Immuno-Oncology Discovery Research; Janssen Research & Development, LLC, Spring House, PA 19477, USA.
authors.forename: Douglas H
authors.initials: DH
authors.lastname: Yamada
authors.affiliation: Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Cameron R
authors.initials: CR
authors.lastname: Cunningham
authors.affiliation: 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.
authors.forename: Elizabeth J
authors.initials: EJ
authors.lastname: Tarling
authors.affiliation: Center for Advanced Medical Imaging Sciences, Department of Radiology, Massachusetts General Hospital, Boston, MA 02114, USA.
authors.forename: Moses Q
authors.initials: MQ
authors.lastname: Wilks
authors.affiliation: Department of Pathology and Laboratory Medicine, University of California, Los Angeles, David Geffen School of Medicine, Los Angeles, CA 90095, USA.
authors.forename: David
authors.initials: D
authors.lastname: Casero
authors.affiliation: 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.
authors.forename: David H
authors.initials: DH
authors.lastname: Gray
authors.affiliation: Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Amy K
authors.initials: AK
authors.lastname: Yu
authors.affiliation: Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Eric S
authors.initials: ES
authors.lastname: Wang
authors.affiliation: 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.
authors.forename: David G
authors.initials: DG
authors.lastname: Brooks
authors.affiliation: Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Ren
authors.initials: R
authors.lastname: Sun
authors.affiliation: 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.
authors.forename: Scott G
authors.initials: SG
authors.lastname: Kitchen
authors.affiliation: Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Ting-Ting
authors.initials: TT
authors.lastname: Wu
authors.affiliation: 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.
authors.forename: Karen
authors.initials: K
authors.lastname: Reue
authors.affiliation: Department of Immunology, University of Washington, 750 Republican Street, Box 358059, Seattle, WA 98109, USA.
authors.forename: Daniel B
authors.initials: DB
authors.lastname: Stetson
authors.affiliation: 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.
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Bensinger
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002784:Cholesterol / Q000378:metabolism*; D006801:Humans; D007113:Immunity, Innate; D000068576:Interferon beta-1b; D007371:Interferon-gamma / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism; D008798:Mevalonic Acid / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D015398:Signal Transduction; D051780:Sterol Regulatory Element Binding Protein 1 / Q000378:metabolism; D051782:Sterol Regulatory Element Binding Protein 2 / Q000378:metabolism
chemical_list: D008565:Membrane Proteins; C497388:Srebf1 protein, mouse; C497391:Srebf2 protein, mouse; D051780:Sterol Regulatory Element Binding Protein 1; D051782:Sterol Regulatory Element Binding Protein 2; D000068576:Interferon beta-1b; D007371:Interferon-gamma; D002784:Cholesterol; D008798:Mevalonic Acid