Systematic Discovery of TLR Signaling Components Delineates Viral-Sensing Circuits

被引：159

作者：

Chevrier, Nicolas ^{[1
,2
,3
,4
]}

Mertins, Philipp ^{[1
]}

Artyomov, Maxim N. ^{[1
,7
]}

Shalek, Alex K. ^{[8
,9
,11
]}

Iannacone, Matteo ^{[5
,6
,13
]}

Ciaccio, Mark F. ^{[10
,12
]}

Gat-Viks, Irit ^{[1
,7
]}

Tonti, Elena ^{[5
,6
,13
]}

DeGrace, Marciela M. ^{[1
,2
,3
]}

Clauser, Karl R. ^{[1
]}

Garber, Manuel ^{[1
]}

Eisenhaure, Thomas M. ^{[1
,2
]}

Yosef, Nir ^{[1
,7
]}

Robinson, Jacob ^{[8
,9
,11
]}

Sutton, Amy ^{[8
,9
,11
]}

Andersen, Mette S. ^{[8
,9
,11
]}

Root, David E. ^{[1
]}

von Andrian, Ulrich ^{[5
,6
]}

Jones, Richard B. ^{[10
,12
]}

Park, Hongkun ^{[8
,9
,11
]}

Carr, Steven A. ^{[1
]}

Regev, Aviv ^{[1
,7
]}

Amit, Ido ^{[1
,2
,3
,7
]}

Hacohen, Nir ^{[1
,2
,3
]}

机构：

[1] Broad Inst MIT& Harvard, Cambridge Ctr 7, Cambridge, MA 02142 USA

[2] Massachusetts Gen Hosp, Ctr Immunol & Inflammatory Dis, Charlestown, MA 02129 USA

[3] Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA

[4] Harvard Univ, Sch Med, Div Med Sci, Grad Program Immunol, Boston, MA 02115 USA

[5] Harvard Univ, Sch Med, Immune Dis Inst, Boston, MA 02115 USA

[6] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA

[7] MIT, Howard Hughes Med Inst, Dept Biol, Cambridge, MA 02142 USA

[8] Harvard Univ, Dept Chem, Cambridge, MA 02138 USA

[9] Harvard Univ, Dept Chem Biol, Cambridge, MA 02138 USA

[10] Univ Chicago, Ben May Dept Canc Res, Chicago, IL 60637 USA

[11] Harvard Univ, Dept Phys, Cambridge, MA 02138 USA

[12] Univ Chicago, Inst Genom & Syst Biol, Chicago, IL 60637 USA

[13] Ist Sci San Raffaele, Div Immunol Infect Dis & Transplantat, I-20132 Milan, Italy

来源：

CELL | 2011年 / 147卷 / 04期

关键词：

POLO-LIKE KINASES; BETA GENE-EXPRESSION; TOLL-LIKE RECEPTORS; INTERFERON-BETA; AUTOIMMUNE-DISEASES; I INTERFERON; CELLS; INHIBITORS; RESPONSES; PHOSPHORYLATION;

D O I：

10.1016/j.cell.2011.10.022

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：

Deciphering the signaling networks that underlie normal and disease processes remains a major challenge. Here, we report the discovery of signaling components involved in the Toll-like receptor (TLR) response of immune dendritic cells (DCs), including a previously unkown pathway shared across mammalian antiviral responses. By combining transcriptional profiling, genetic and small-molecule perturbations, and phosphoproteomics, we uncover 35 signaling regulators, including 16 known regulators, involved in TLR signaling. In particular, we find that Polo-like kinases (Plk) 2 and 4 are essential components of antiviral pathways in vitro and in vivo and activate a signaling branch involving a dozen proteins, among which is Tnfaip2, a gene associated with autoimmune diseases but whose role was unknown. Our study illustrates the power of combining systematic measurements and perturbations to elucidate complex signaling circuits and discover potential therapeutic targets.

引用

页码：853 / 867

页数：15

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