Limiting Cholesterol Biosynthetic Flux Spontaneously Engages Type I IFN Signaling.
Cell
; 163(7): 1716-29, 2015 Dec 17.
Article
em En
| MEDLINE
| ID: mdl-26686653
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.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Transdução de Sinais
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Colesterol
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Interferon gama
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Imunidade Inata
Limite:
Animals
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Humans
Idioma:
En
Revista:
Cell
Ano de publicação:
2015
Tipo de documento:
Article
País de afiliação:
Estados Unidos