Dataset Information


Limiting cholesterol biosynthetic flux engages type I IFN signaling in a STING-dependent manner

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 rapidly 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. shRNA to SREBF1 (shSREBP1) or SREBF2 (shSREBP2) were stably introduced via 3rd generation lentivirus into human THP1 monocytic cells under puromycin selection. Non-targeting shRNA scramble was used for a control (shControl). shControl, shSREBP1 and shSREBP2 modified cell types were analyzed by RNA-seq in duplicate.

ORGANISM(S): Homo sapiens  

SUBMITTER: Anjie Zhen   Quan Zhu  Steven Bensinger  Nicholas Wu  Ting-Ting Wu  Moses Q Wilks  Gubpreet Brar  Amy Yu  Steven J Bensinger  Daniel Stetson  Ren Sun  Karen Reue  Joseph Argus  Laurent Vergnes  Kevin Williams  Elizabth Gray  Douglas Yamada  David Casero  Cameron Cunningham  Autumn G York  Scott Kitchen  David Gray  David Brooks 

PROVIDER: E-GEOD-73942 | ArrayExpress | 2015-12-10



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