title: 25-Hydroxycholesterol activates the integrated stress response to reprogram transcription and translation in macrophages.
abstract: 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.
authors.affiliation: From the Departments of Cellular and Molecular Medicine.
authors.forename: Norihito
authors.initials: N
authors.lastname: Shibata
authors.forename: Aaron F
authors.initials: AF
authors.lastname: Carlin
authors.forename: Nathanael J
authors.initials: NJ
authors.lastname: Spann
authors.forename: Kaoru
authors.initials: K
authors.lastname: Saijo
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Morello
authors.forename: Jeffrey G
authors.initials: JG
authors.lastname: McDonald
authors.forename: Casey E
authors.initials: CE
authors.lastname: Romanoski
authors.forename: Mano R
authors.initials: MR
authors.lastname: Maurya
authors.forename: Minna U
authors.initials: MU
authors.lastname: Kaikkonen
authors.forename: Michael T
authors.initials: MT
authors.lastname: Lam
authors.forename: Andrea
authors.initials: A
authors.lastname: Crotti
authors.forename: Donna
authors.initials: D
authors.lastname: Reichart
authors.forename: Jesse N
authors.initials: JN
authors.lastname: Fox
authors.forename: Oswald
authors.initials: O
authors.lastname: Quehenberger
authors.forename: Christian R H
authors.initials: CR
authors.lastname: Raetz
authors.forename: M Cameron
authors.initials: MC
authors.lastname: Sullards
authors.forename: Robert C
authors.initials: RC
authors.lastname: Murphy
authors.forename: Alfred H
authors.initials: AH
authors.lastname: Merrill
authors.forename: H Alex
authors.initials: HA
authors.lastname: Brown
authors.forename: Edward A
authors.initials: EA
authors.lastname: Dennis
authors.forename: Eoin
authors.initials: E
authors.lastname: Fahy
authors.forename: Shankar
authors.initials: S
authors.lastname: Subramaniam
authors.forename: Douglas R
authors.initials: DR
authors.lastname: Cavener
authors.forename: Deborah H
authors.initials: DH
authors.lastname: Spector
authors.forename: David W
authors.initials: DW
authors.lastname: Russell
authors.forename: Christopher K
authors.initials: CK
authors.lastname: Glass
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology; D002788:Cholesterol Esters / Q000378:metabolism; D020869:Gene Expression Profiling; D006888:Hydroxycholesterols / Q000378:metabolism / Q000494:pharmacology*; D000071518:Liver X Receptors; D008264:Macrophages / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism* / Q000821:virology; D051379:Mice; D008810:Mice, Inbred C57BL; D018146:Muromegalovirus / Q000502:physiology; D057093:Orphan Nuclear Receptors / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D014176:Protein Biosynthesis / Q000187:drug effects*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D013107:Sphingolipids / Q000378:metabolism; D051779:Sterol Regulatory Element Binding Proteins / Q000037:antagonists & inhibitors; D014158:Transcription, Genetic / Q000187:drug effects*
chemical_list: D002788:Cholesterol Esters; D006888:Hydroxycholesterols; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D013107:Sphingolipids; D051779:Sterol Regulatory Element Binding Proteins; C007997:25-hydroxycholesterol
keywords: 25-Hydroxycholesterol; Amino Acid; GCN2; Lipids; MCMV; Macrophages; Oxidative Stress; Stress Response; Translation; eIF2-α