TY - JOUR
T1 - 25-Hydroxycholesterol activates the integrated stress response to reprogram transcription and translation in macrophages
AU - Shibata, Norihito
AU - Carlin, Aaron F.
AU - Spann, Nathanael J.
AU - Saijo, Kaoru
AU - Morello, Christopher S.
AU - McDonald, Jeffrey G.
AU - Romanoski, Casey E.
AU - Maurya, Mano R.
AU - Kaikkonen, Minna U.
AU - Lam, Michael T.
AU - Crotti, Andrea
AU - Reichart, Donna
AU - Fox, Jesse N.
AU - Quehenberger, Oswald
AU - Raetz, Christian R H
AU - Cameron Sullards, M.
AU - Murphy, Robert C.
AU - Merrill, Alfred H.
AU - Alex Brown, H.
AU - Dennis, Edward A.
AU - Fahy, Eoin
AU - Subramaniam, Shankar
AU - Cavener, Douglas R.
AU - Spector, Deborah H.
AU - Russell, David W.
AU - Glassa, Christopher K.
PY - 2013/12/13
Y1 - 2013/12/13
N2 - 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.
AB - 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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U2 - 10.1074/jbc.M113.519637
DO - 10.1074/jbc.M113.519637
M3 - Article
C2 - 24189069
AN - SCOPUS:84890352480
SN - 0021-9258
VL - 288
SP - 35812
EP - 35823
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 50
ER -