Interferon-mediated reprogramming of membrane cholesterol to evade bacterial toxins
Zhou Q, Chi X, Lee M, Hsieh W, Mkrtchyan J, Feng A, He C, York A, Bui V, Kronenberger E, Ferrari A, Daly, A, Tarling E, Damoiseaux R, Scumpia P, Smale S, Williams K, Tontonoz P, Bensinger S (2020). Nat Immunol. 21:746-755.
Cholesterol Dependent Cytoysins (CDCs) are bacterial toxins or virulence factors that punch holes in the membranes of cells and contribute to the destruction of infected tissues. In this study, we discovered that interferons, key cytokines mobilized to control infections, induce protection of cells from CDCs. This protective state depended on interferons' ability to produce a lipid, 25-hydroxycholesterol, that rapidly reprograms cellular cholesterol homeostasis. Ongoing work in the laboratory is focused on testing whether this metabolic pathway can be manipulated to spare tissues from destruction in infections such as deadly necrotizing fasciitis.
Toll-like receptors induce signal specific reprogramming of the macrophage lipidome
Hsieh W, Zhou Q, York A, Williams K, Scumpia P, Kronenberger E, Hoi X, Baolong S, Chi X, Bui V, Khialeeva E, Kaplan A, MinSon, Y, Divakaruni, A, Sun J, Smale S, Flavell R, Bensinger S (2020).
Cell Metab. 32:128-143.
Macrophages are critical immune cells that protect the body from infections, clear cellular debris and foreign material, and facilitate wound healing. To facilitate these different reponses, macrophages are armed with an array of receptors that detect foreign invaders, cellular damage, and repair signals. It has been shown that macrophages rapidly reprogram their lipid metabolism when activated. However, the extent to which these amazing cells reshape their lipid composition and whether they acquire a preferred effector lipidome, irrespective of the activation signal, was largely unknown. In this study, we applied leading-edge lipidomics to define how different activation signals reshape the macrophage lipidome. Remarkably, we found that macrophages profoundly and rapidly alter their lipid composition. Provocatively, these changes occurred in a signal-specific manner, indicating that these changes are necessary for different effector functions. On-going lab studies are using genetic approaches to test this idea.
Limiting cholesterol biosynthetic flux engages type I IFN signaling in a STING-dependent manner
York A, Argus J, Williams K, Brar G, Vergnes L, Gray E, Zhen A, Wu N, Yamada D, Cunningham C, Wilks M, Casero D, Gray D, Yu A, Brooks D, Sun R, Kitchen S, Wu T, Reue K, Stetson D and Bensinger S (2015).
Alterations in lipid metabolism are often observed in many diseases, ranging from metabolic diseases such as atherosclerosis to viral and bacterial infections. Inflammation is often correlated with these changes in lipid homeostasis, and it has been proposed that the inflammatory process reprograms the lipid composition of cells. Sometimes this reprogramming of lipid metabolism can be beneficial, as in the case of infections, or harmful in the case of metabolic diseases. The molecular circuitry linking inflammatory responses with lipid metabolic machinery remains enigmatic. In this study, we discovered that limiting a cell's ability to make cholesterol results in heightened type I IFN responses. We also show that IFN signals reduce cellular cholesterol biosynthesis. Our search for molecular circuitry linking cholesterol metabolism with IFN responses revealed an essential role for an intracellular signaling molecule called STING. The STING pathway is able to transduce information about the metabolic fitness of the cholesterol synthetic pathways. Ongoing studies in the lab are hunting for "how" STING senses changes in cholesterol levels in a cell and "why" cholesterol homeostasis would be specifically wired to the type I IFN response.
Development and Application of Fatty Acid Source Analysis (FASA), A New Model for Quantifying Fatty Acid Metabolism Using Stable Isotope Labeling
Argus J, Wilks M, Zhou Q, Hsieh W-Y, Khialeeva E, Hoi X-P, Bui V, Xu S, Yu A, Wang E, Herschman H, Williams K, Bensinger S (2018).
Cell Rep. Dec 10:2919-2934.
Fatty acids are an essential element of the complex lipids used by a cell to produce and maintain cellular membranes. Cells use a wide variety of fatty acids, ranging from a relatively short 14 carbons to greater than 32 carbons in length, to create complex lipids. Additionally, fatty acids can be desaturated to introduce new biophysical and biochemical properties. The origin of these lipid building blocks and the complex molecular machinery that generates this diversity of fatty acid species for any given cell remains challenging to decipher. In this study, we use stable isotope tracers in combination with mass spectrometry and mathematical modeling to develop a new way to deconvolute the origin of a given fatty acid within the cell. We use this new model to follow how fatty acids are lengthened and desaturated in response to changes in metabolic demands or inflammation. Current work in the lab is leveraging this approach to understand how cells and tissues synthesize, import, and ultimately use lipids to create complex lipids. Want to learn more about how we created this new model? Click on the link below to read the full manuscript.