25-Hydroxycholesterol Activates the Integrated Stress Response to Reprogram Transcription and Translation in Macrophages

Overview

Journal J Biol Chem

Specialty Biochemistry

Date 2013 Nov 6

PMID 24189069

Citations 45

Authors

Norihito Shibata

Aaron F Carlin

Nathanael J Spann

Kaoru Saijo

Christopher S Morello

Jeffrey G McDonald

Casey E Romanoski

Mano R Maurya

Minna U Kaikkonen

Michael T Lam

Andrea Crotti

Donna Reichart

Jesse N Fox

Oswald Quehenberger

Christian R H Raetz

M Cameron Sullards

Robert C Murphy

Alfred H Merrill Jr

H Alex Brown

Edward A Dennis

Eoin Fahy

Shankar Subramaniam

Douglas R Cavener

Deborah H Spector

David W Russell

Christopher K Glass

Affiliations

Soon will be listed here.

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.

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