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Article: Limiting Cholesterol Biosynthetic Flux Spontaneously Engages Type i IFN Signaling

TitleLimiting Cholesterol Biosynthetic Flux Spontaneously Engages Type i IFN Signaling
Authors
Issue Date2015
Citation
Cell, 2015, v. 163, n. 7, p. 1716-1729 How to Cite?
Abstract© 2015 Elsevier Inc. All rights reserved. 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.
Persistent Identifierhttp://hdl.handle.net/10722/285935
ISSN
2023 Impact Factor: 45.5
2023 SCImago Journal Rankings: 24.342
PubMed Central ID
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorYork, Autumn G.-
dc.contributor.authorWilliams, Kevin J.-
dc.contributor.authorArgus, Joseph P.-
dc.contributor.authorZhou, Quan D.-
dc.contributor.authorBrar, Gurpreet-
dc.contributor.authorVergnes, Laurent-
dc.contributor.authorGray, Elizabeth E.-
dc.contributor.authorZhen, Anjie-
dc.contributor.authorWu, Nicholas C.-
dc.contributor.authorYamada, Douglas H.-
dc.contributor.authorCunningham, Cameron R.-
dc.contributor.authorTarling, Elizabeth J.-
dc.contributor.authorWilks, Moses Q.-
dc.contributor.authorCasero, David-
dc.contributor.authorGray, David H.-
dc.contributor.authorYu, Amy K.-
dc.contributor.authorWang, Eric S.-
dc.contributor.authorBrooks, David G.-
dc.contributor.authorSun, Ren-
dc.contributor.authorKitchen, Scott G.-
dc.contributor.authorWu, Ting Ting-
dc.contributor.authorReue, Karen-
dc.contributor.authorStetson, Daniel B.-
dc.contributor.authorBensinger, Steven J.-
dc.date.accessioned2020-08-18T04:57:01Z-
dc.date.available2020-08-18T04:57:01Z-
dc.date.issued2015-
dc.identifier.citationCell, 2015, v. 163, n. 7, p. 1716-1729-
dc.identifier.issn0092-8674-
dc.identifier.urihttp://hdl.handle.net/10722/285935-
dc.description.abstract© 2015 Elsevier Inc. All rights reserved. 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.-
dc.languageeng-
dc.relation.ispartofCell-
dc.titleLimiting Cholesterol Biosynthetic Flux Spontaneously Engages Type i IFN Signaling-
dc.typeArticle-
dc.description.naturelink_to_OA_fulltext-
dc.identifier.doi10.1016/j.cell.2015.11.045-
dc.identifier.pmid26686653-
dc.identifier.pmcidPMC4783382-
dc.identifier.scopuseid_2-s2.0-84950247027-
dc.identifier.volume163-
dc.identifier.issue7-
dc.identifier.spage1716-
dc.identifier.epage1729-
dc.identifier.eissn1097-4172-
dc.identifier.isiWOS:000366854200018-
dc.identifier.f1000726028135-
dc.identifier.issnl0092-8674-

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