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

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, H. Alex Brown, Edward A. DennisEoin Fahy, Shankar Subramaniam, Douglas R. Cavener, Deborah H. Spector, David W. Russell, Christopher K. Glassa

Research output: Contribution to journalArticle

32 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)35812-35823
Number of pages12
JournalJournal of Biological Chemistry
Volume288
Issue number50
DOIs
StatePublished - Dec 13 2013

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Shibata, N., Carlin, A. F., Spann, N. J., Saijo, K., Morello, C. S., McDonald, J. G., Romanoski, C. E., Maurya, M. R., Kaikkonen, M. U., Lam, M. T., Crotti, A., Reichart, D., Fox, J. N., Quehenberger, O., Raetz, C. R. H., Cameron Sullards, M., Murphy, R. C., Merrill, A. H., Alex Brown, H., ... Glassa, C. K. (2013). 25-Hydroxycholesterol activates the integrated stress response to reprogram transcription and translation in macrophages. Journal of Biological Chemistry, 288(50), 35812-35823. https://doi.org/10.1074/jbc.M113.519637