The Transcription Factor STAT-1 Couples Macrophage Synthesis of 25-Hydroxycholesterol to the Interferon Antiviral Response

被引：323

作者：

Blanc, Mathieu ^{[1
]}

Hsieh, Wei Yuan ^{[1
]}

Robertson, Kevin A. ^{[1
,2
]}

Kropp, Kai A. ^{[1
]}

Forster, Thorsten ^{[1
]}

Shui, Guanghou ^{[3
,4
]}

Lacaze, Paul ^{[1
]}

Watterson, Steven ^{[1
,2
]}

Griffiths, Samantha J. ^{[1
]}

Spann, Nathanael J. ^{[5
]}

Meljon, Anna ^{[6
]}

Talbot, Simon ^{[1
]}

Krishnan, Kathiresan ^{[7
]}

Covey, Douglas F. ^{[7
]}

Wenk, Markus R. ^{[3
,4
]}

Craigon, Marie ^{[1
]}

Ruzsics, Zsolts ^{[8
]}

Haas, Juergen ^{[1
]}

Angulo, Ana ^{[9
]}

Griffiths, William J. ^{[6
]}

Glass, Christopher K. ^{[5
]}

Wang, Yuqin ^{[6
]}

Ghazal, Peter ^{[1
,2
]}

机构：

[1] Univ Edinburgh, Div Pathway Med & Edinburgh Infect Dis, Edinburgh EH16 4SB, Midlothian, Scotland

[2] Univ Edinburgh, SynthSys Synthet & Syst Biol, Edinburgh EH9 3JD, Midlothian, Scotland

[3] Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Biochem, Singapore 117597, Singapore

[4] Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Biol Sci, Singapore 117597, Singapore

[5] Univ Calif San Diego, Dept Mol Biol, La Jolla, CA 92093 USA

[6] Swansea Univ, Coll Med, Inst Mass Spectrometry, Swansea SA2 8PP, W Glam, Wales

[7] Washington Univ, Sch Med, Dept Dev Biol, St Louis, MO 63011 USA

[8] Univ Munich, Max Von Pettenkofer Inst, Genzentrum, D-81377 Munich, Germany

[9] Inst Invest Biomed August Pi & Sunyer, Fac Med, Barcelona 08036, Spain

来源：

IMMUNITY | 2013年 / 38卷 / 01期

基金：

英国生物技术与生命科学研究理事会; 英国工程与自然科学研究理事会; 英国惠康基金;

关键词：

STEROL-REGULATED TRANSPORT; FATTY-ACID SYNTHESIS; ENDOPLASMIC-RETICULUM; CYTOMEGALOVIRUS-INFECTION; CHOLESTEROL-SYNTHESIS; CELL-MIGRATION; IN-VIVO; BINDING; PROTEIN; PRENYLATION;

D O I：

10.1016/j.immuni.2012.11.004

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

100102 ;

摘要：

Recent studies suggest that the sterol metabolic network participates in the interferon (IFN) antiviral response. However, the molecular mechanisms linking IFN with the sterol network and the identity of sterol mediators remain unknown. Here we report a cellular antiviral role for macrophage production of 25-hydroxycholesterol (cholest-5-en-3 beta,25-diol, 25HC) as a component of the sterol metabolic network linked to the IFN response via Stat1. By utilizing quantitative metabolome profiling of all naturally occurring oxysterols upon infection or IFN-stimulation, we reveal 25HC as the only macrophage-synthesized and -secreted oxysterol. We show that 25HC can act at multiple levels as a potent paracrine inhibitor of viral infection for a broad range of viruses. We also demonstrate, using transcriptional regulatory-network analyses, genetic interventions and chromatin immunoprecipitation experiments that Stat1 directly coupled Ch25h regulation to IFN in macrophages. Our studies describe a physiological role for 25HC as a sterol-lipid effector of an innate immune pathway.

引用

页码：106 / 118

页数：13

共 41 条

[1] Cholesterol and 25-hydroxycholesterol inhibit activation of SREBPs by different mechanisms, both involving SCAP and insigs [J].