期刊
CELL
卷 163, 期 7, 页码 1716-1729出版社
CELL PRESS
DOI: 10.1016/j.cell.2015.11.045
关键词
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资金
- NCI Cancer Center Support Grant [P3016042-35]
- California HIV/AIDS Research Program Training Fellowship [D12-LA-351]
- UCLA Dissertation Year Fellowship
- NIH CBI Grant [T32 GM008469]
- UCLA Molecular Biology Philip Whitcome Pre-Doctoral Fellowship
- Interdisciplinary Training in Virology and Gene Therapy Training Grant [NIH T32 AI 060567]
- Cancer Research Institute Fellowship Program
- NIH [HL 116181, P01 HL028481, P01 HL090553, AI093768, HL126556]
- UCLA CTSI-DRC [UL1TR000124]
- NCI [RO1 CA177322]
- NIDCR [RO1 DE023519]
- Lupus Research Institute
- NIH NCRR [S10RR026744]
- [R01 AI085043]
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.
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