25-Hydroxycholesterol activates the integrated stress response to reprogram transcription and translation in macrophages.

Shibata N, Carlin AF, Spann NJ, Saijo K, Morello CS, McDonald JG, Romanoski CE, Maurya MR, Kaikkonen MU, Lam MT, Crotti A, Reichart D, Fox JN, Quehenberger O, Raetz CR, Sullards MC, Murphy RC, Merrill AH, Brown HA, Dennis EA, Fahy E, Subramaniam S, Cavener DR, Spector DH, Russell DW, Glass CK
J Biol Chem. 2013 288 (50): 35812-23

PMID: 24189069 · PMCID: PMC3861632 · DOI:10.1074/jbc.M113.519637

25-Hydroxycholesterol (25OHC) is an enzymatically derived oxidation product of cholesterol that modulates lipid metabolism and immunity. 25OHC is synthesized in response to interferons and exerts broad antiviral activity by as yet poorly characterized mechanisms. To gain further insights into the basis for antiviral activity, we evaluated time-dependent responses of the macrophage lipidome and transcriptome to 25OHC treatment. In addition to altering specific aspects of cholesterol and sphingolipid metabolism, we found that 25OHC activates integrated stress response (ISR) genes and reprograms protein translation. Effects of 25OHC on ISR gene expression were independent of liver X receptors and sterol-response element-binding proteins and instead primarily resulted from activation of the GCN2/eIF2α/ATF4 branch of the ISR pathway. These studies reveal that 25OHC activates the integrated stress response, which may contribute to its antiviral activity.

MeSH Terms (17)

Animals Bone Marrow Cells Cholesterol Esters Gene Expression Profiling Hydroxycholesterols Liver X Receptors Macrophages Mice Mice, Inbred C57BL Muromegalovirus Orphan Nuclear Receptors Oxidative Stress Protein Biosynthesis Signal Transduction Sphingolipids Sterol Regulatory Element Binding Proteins Transcription, Genetic

Connections (1)

This publication is referenced by other Labnodes entities: