The prohibitin complex regulates macrophage fatty acid composition, plasma membrane packing, and lipid raft-mediated inflammatory signaling.

Autor: Matthews CEP; Department of Pharmacology and Toxicology, Brody School of Medicine, East Carolina University, Greenville, NC, United States., Fussner LA; Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Internal Medicine, The Ohio State University, Columbus, OH, United States., Yaeger M; Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Internal Medicine, The Ohio State University, Columbus, OH, United States., Aloor JJ; Diabetes and Obesity Institute, Department of Physiology, East Carolina University, Greenville, NC, United States., Reece SW; Department of Pharmacology and Toxicology, Brody School of Medicine, East Carolina University, Greenville, NC, United States., Kilburg-Basnyat BJ; Department of Pharmacology and Toxicology, Brody School of Medicine, East Carolina University, Greenville, NC, United States., Varikuti S; Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Internal Medicine, The Ohio State University, Columbus, OH, United States., Luo B; Department of Pharmacology and Toxicology, Brody School of Medicine, East Carolina University, Greenville, NC, United States., Inks M; Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Internal Medicine, The Ohio State University, Columbus, OH, United States., Sergin S; Department of Food Science and Human Nutrition, Michigan State University, East Lansing, MI, United States., Schmidt CA; Diabetes and Obesity Institute, Department of Physiology, East Carolina University, Greenville, NC, United States., Neufer PD; Diabetes and Obesity Institute, Department of Physiology, East Carolina University, Greenville, NC, United States., Pennington ER; Department of Nutrition, Gillings School of Global Public Health and School of Medicine, University of North Carolina, Chapel Hill, NC, United States., Fisher-Wellman KH; Diabetes and Obesity Institute, Department of Physiology, East Carolina University, Greenville, NC, United States., Chowdhury SM; Department of Chemistry and Biochemistry, University of Texas at Arlington, Arlington, TX, United States., Fessler MB; Immunity, Inflammation and Disease Laboratory, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, NC, United States., Fenton JI; Department of Food Science and Human Nutrition, Michigan State University, East Lansing, MI, United States., Anderson EJ; Department of Pharmaceutical Sciences and Experimental Therapeutics, College of Pharmacy, FOE Diabetes Research Center, University of Iowa, Iowa City, IA, United States., Shaikh SR; Department of Nutrition, Gillings School of Global Public Health and School of Medicine, University of North Carolina, Chapel Hill, NC, United States., Gowdy KM; Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Internal Medicine, The Ohio State University, Columbus, OH, United States. Electronic address: kymberly.gowdy@osumc.edu.
Jazyk: angličtina
Zdroj: Prostaglandins, leukotrienes, and essential fatty acids [Prostaglandins Leukot Essent Fatty Acids] 2023 Mar; Vol. 190, pp. 102540. Date of Electronic Publication: 2023 Jan 19.
DOI: 10.1016/j.plefa.2023.102540
Abstrakt: Prohibitins (PHB1 and PHB2) are ubiquitously expressed proteins which play critical roles in multiple biological processes, and together form the ring-like PHB complex found in phospholipid-rich cellular compartments including lipid rafts. Recent studies have implicated PHB1 as a mediator of fatty acid transport as well as a membrane scaffold mediating B lymphocyte and mast cell signal transduction. However, the specific role of PHBs in the macrophage have not been characterized, including their role in fatty acid uptake and lipid raft-mediated inflammatory signaling. We hypothesized that the PHB complex regulates macrophage inflammatory signaling through the formation of lipid rafts. To evaluate our hypothesis, RAW 264.7 macrophages were transduced with shRNA against PHB1, PHB2, or scrambled control (Scr), and then stimulated with lipopolysaccharide (LPS) or tumor necrosis factor-alpha (TNF-α), which activate lipid raft-dependent receptor signaling (CD14/TLR4 and TNFR1, respectively). PHB1 knockdown was lethal, whereas PHB2 knockdown (PHB2kd), which also resulted in decreased PHB1 expression, led to attenuated nuclear factor-kappa-B (NF-κB) activation and subsequent cytokine and chemokine production. PHB2kd macrophages also had decreased cell surface TNFR1, CD14, TLR4, and lipid raft marker ganglioside GM1 at baseline and post-stimuli. Post-LPS, PHB2kd macrophages did not increase the concentration of cellular saturated, monounsaturated, and polyunsaturated fatty acids. This was accompanied by decreased lipid raft formation and modified plasma membrane molecular packing, further supporting the PHB complex's importance in lipid raft formation. Taken together, these data suggest a critical role for PHBs in regulating macrophage inflammatory signaling via maintenance of fatty acid composition and lipid raft structure. SUMMARY: Prohibitins are proteins found in phospholipid-rich cellular compartments, including lipid rafts, that play important roles in signaling, transcription, and multiple other cell functions. Macrophages are key cells in the innate immune response and the presence of membrane lipid rafts is integral to signal transduction, but the role of prohibitins in macrophage lipid rafts and associated signaling is unknown. To address this question, prohibitin knockdown macrophages were generated and responses to lipopolysaccharide and tumor necrosis factor-alpha, which act through lipid raft-dependent receptors, were analyzed. Prohibitin knockdown macrophages had significantly decreased cytokine and chemokine production, transcription factor activation, receptor expression, lipid raft assembly and membrane packing, and altered fatty acid remodeling. These data indicate a novel role for prohibitins in macrophage inflammatory signaling through regulation of fatty acid composition and lipid raft formation.
Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Kymberly M. Gowdy reports financial support was provided by National Institutes of Health. Saame Raza Shaikh reports financial support was provided by National Institutes of Health. Christine E. Psaltis Matthews reports financial support was provided by American Association of Immunologists Inc. Christine E. Psaltis Matthews reports financial support was provided by Burroughs Wellcome Fund. Ethan J. Anderson reports financial support was provided by US Department of Defense. Ethan J. Anderson reports financial support was provided by American Heart Association Inc. Michael B. Fessler reports financial support was provided by National Institute of Environmental Health Sciences.
(Copyright © 2023 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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