Limiting Cholesterol Biosynthetic Flux Spontaneously Engages Type I IFN Signaling

被引：340

作者：

York, Autumn G. ^{[1
]}

Williams, Kevin J. ^{[2
]}

Argus, Joseph P. ^{[1
]}

Zhou, Quan D. ^{[1
]}

Brar, Gurpreet ^{[1
]}

Vergnes, Laurent ^{[4
]}

Gray, Elizabeth E.

Zhen, Anjie ^{[5
,7
,8
]}

Wu, Nicholas C. ^{[1
,9
]}

Yamada, Douglas H.

Cunningham, Cameron R. ^{[2
]}

Tarling, Elizabeth J. ^{[6
,9
]}

Wilks, Moses Q. ^{[11
]}

Casero, David ^{[3
]}

Gray, David H. ^{[2
,9
]}

Yu, Amy K. ^{[1
]}

Wang, Eric S. ^{[1
]}

Brooks, David G. ^{[12
,13
,14
,15
]}

Sun, Ren ^{[1
]}

Kitchen, Scott G. ^{[5
,7
,8
]}

Wu, Ting-Ting ^{[1
]}

Reue, Karen ^{[4
,9
]}

Stetson, Daniel B. ^{[10
]}

Bensinger, Steven J. ^{[1
,2
,3
]}

机构：

[1] Univ Calif Los Angeles, David Geffen Sch Med, Dept Mol & Med Pharmacol, Los Angeles, CA 90095 USA

[2] Univ Calif Los Angeles, Dept Microbiol Immunol & Mol Genet, Los Angeles, CA 90095 USA

[3] Univ Calif Los Angeles, David Geffen Sch Med, Dept Pathol & Lab Med, Los Angeles, CA 90095 USA

[4] Univ Calif Los Angeles, David Geffen Sch Med, Dept Human Genet, Los Angeles, CA 90095 USA

[5] Univ Calif Los Angeles, David Geffen Sch Med, Div Hematol Oncol, Los Angeles, CA 90095 USA

[6] Univ Calif Los Angeles, David Geffen Sch Med, Div Cardiol, Los Angeles, CA 90095 USA

[7] UCLA AIDS Inst, Los Angeles, CA 90095 USA

[8] Eli & Edythe Broad Ctr Regenerat Med & Stem Cell, Los Angeles, CA 90095 USA

[9] Univ Calif Los Angeles, Inst Mol Biol, Los Angeles, CA 90095 USA

[10] Univ Washington, Dept Immunol, Seattle, WA 98109 USA

[11] Massachusetts Gen Hosp, Dept Radiol, Ctr Adv Med Imaging Sci, Boston, MA 02114 USA

[12] Univ Hlth Network, Princess Margaret Canc Ctr, Immune Therapy Program, Toronto, ON M5G 2M9, Canada

[13] Univ Toronto, Dept Immunol, Toronto, ON M5S 1A8, Canada

[14] Immunooncol Discovery Res, Spring House, PA 19477 USA

[15] Janssen Res & Dev LLC, Spring House, PA 19477 USA

来源：

CELL | 2015年 / 163卷 / 07期

关键词：

FATTY-ACID SYNTHESIS; FOAM CELL-FORMATION; MYCOBACTERIUM-TUBERCULOSIS; ENDOPLASMIC-RETICULUM; RECEPTOR AGONISTS; INTERFERON; REPLICATION; MACROPHAGES; PATHWAY; 25-HYDROXYCHOLESTEROL;

D O I：

10.1016/j.cell.2015.11.045

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Cellular lipid requirements are achieved through a combination of biosynthesis and import programs. Using isotope tracer analysis, we show that type I interferon (IFN) signaling shifts the balance of these programs by decreasing synthesis and increasing import of cholesterol and long chain fatty acids. Genetically enforcing this metabolic shift in macrophages is sufficient to render mice resistant to viral challenge, demonstrating the importance of reprogramming the balance of these two metabolic pathways in vivo. Unexpectedly, mechanistic studies reveal that limiting flux through the cholesterol biosynthetic pathway spontaneously engages a type I IFN response in a STING-dependent manner. The upregulation of type I IFNs was traced to a decrease in the pool size of synthesized cholesterol and could be inhibited by replenishing cells with free cholesterol. Taken together, these studies delineate a metabolic-inflammatory circuit that links perturbations in cholesterol biosynthesis with activation of innate immunity.

引用

页码：1716 / 1729

页数：14

共 46 条

[21] Pathogenesis of a Model Gammaherpesvirus in a Natural Host
Hughes, David J.
Kipar, Anja
Sample, Jeffery T.
Stewart, James P.
[J]. JOURNAL OF VIROLOGY, 2010, 84 (08) : 3949 - 3961
[22] STING is an endoplasmic reticulum adaptor that facilitates innate immune signalling
Ishikawa, Hiroki
Barber, Glen N.
[J]. NATURE, 2008, 455 (7213) : 674 - U74
[23] Hepatitis C virus RNA replication is regulated by host geranylgeranylation and fatty acids
Kapadia, SB
Chisari, FV
[J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2005, 102 (07) : 2561 - 2566
[24] Coordinate Stimulation of Macrophages by Microparticles and TLR Ligands Induces Foam Cell Formation
Keyel, Peter A.
Tkacheva, Olga A.
Larregina, Adriana T.
Salter, Russell D.
[J]. JOURNAL OF IMMUNOLOGY, 2012, 189 (09) : 4621 - 4629
[25] Sterol regulatory element-binding proteins are essential for the metabolic programming of effector T cells and adaptive immunity
Kidani, Yoko
Elsaesser, Heidi
Hock, M. Benjamin
Vergnes, Laurent
Williams, Kevin J.
Argus, Joseph P.
Marbois, Beth N.
Komisopoulou, Evangelia
Wilson, Elizabeth B.
Osborne, Timothy F.
Graeber, Thomas G.
Reue, Karen
Brooks, David G.
Bensinger, Steven J.
[J]. NATURE IMMUNOLOGY, 2013, 14 (05) : 489 - +
[26] A cholesterol biosynthesis inhibitor blocks Staphylococcus aureus virulence
Liu, Chia-I
Liu, George Y.
Song, Yongcheng
Yin, Fenglin
Hensler, Mary E.
Jeng, Wen-Yih
Nizet, Victor
Wang, Andrew H. -J.
Oldfield, Eric
[J]. SCIENCE, 2008, 319 (5868) : 1391 - 1394
[27] Interferon-Inducible Cholesterol-25-Hydroxylase Broadly Inhibits Viral Entry by Production of 25-Hydroxycholesterol
Liu, Su-Yang
Aliyari, Roghiyh
Chikere, Kelechi
Li, Guangming
Marsden, Matthew D.
Smith, Jennifer K.
Pernet, Olivier
Guo, Haitao
Nusbaum, Rebecca
Zack, Jerome A.
Freiberg, Alexander N.
Su, Lishan
Lee, Benhur
Cheng, Genhong
[J]. IMMUNITY, 2013, 38 (01) : 92 - 105
[28] Systems-level metabolic flux profiling identifies fatty acid synthesis as a target for antiviral therapy
Munger, Joshua
Bennett, Bryson D.
Parikh, Anuraag
Feng, Xiao-Jiang
McArdle, Jessica
Rabitz, Herschel A.
Shenk, Thomas
Rabinowitz, Joshua D.
[J]. NATURE BIOTECHNOLOGY, 2008, 26 (10) : 1179 - 1186
[29] Generation of influenza A viruses entirely from cloned cDNAs
Neumann, G
Watanabe, T
Ito, H
Watanabe, S
Goto, H
Gao, P
Hughes, M
Perez, DR
Donis, R
Hoffmann, E
Hobom, G
Kawaoka, Y
[J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1999, 96 (16) : 9345 - 9350
[30] Cholesterol catabolism as a therapeutic target in Mycobacterium tuberculosis
Ouellet, Hugues
Johnston, Jonathan B.
de Montellano, Paul R. Ortiz
[J]. TRENDS IN MICROBIOLOGY, 2011, 19 (11) : 530 - 539

← 1 2 3 4 5 →