Systematic discovery of TLR signaling components delineates viral-sensing circuits

Nicolas Chevrier; Philipp Mertins; Maxim N. Artyomov; Alex K. Shalek; Matteo Iannacone; Mark F. Ciaccio; Irit Gat-Viks; Elena Tonti; Marciela M. DeGrace; Karl R. Clauser; Manuel Garber; Thomas M. Eisenhaure; Nir Yosef; Jacob Robinson; Amy Sutton; Mette S. Andersen; David E. Root; Ulrich von Andrian; Richard B. Jones; Hongkun Park; Steven A. Carr; Aviv Regev; Ido Amit; Nir Hacohen

doi:https://doi.org/10.1016/j.cell.2011.10.022

Systematic discovery of TLR signaling components delineates viral-sensing circuits

Nicolas Chevrier, Philipp Mertins, Maxim N. Artyomov, Alex K. Shalek, Matteo Iannacone, Mark F. Ciaccio, Irit Gat-Viks, Elena Tonti, Marciela M. DeGrace, Karl R. Clauser, Manuel Garber, Thomas M. Eisenhaure, Nir Yosef, Jacob Robinson, Amy Sutton, Mette S. Andersen, David E. Root, Ulrich von Andrian, Richard B. Jones, Hongkun ParkSteven A. Carr, Aviv Regev, Ido Amit, Nir Hacohen

Research output: Contribution to journal › Article › peer-review

Abstract

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.

Original language	English
Pages (from-to)	853-867
Number of pages	15
Journal	Cell
Volume	147
Issue number	4
DOIs	https://doi.org/10.1016/j.cell.2011.10.022
State	Published - 11 Nov 2011
Externally published	Yes

All Science Journal Classification (ASJC) codes

General Biochemistry,Genetics and Molecular Biology

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Chevrier, N., Mertins, P., Artyomov, M. N., Shalek, A. K., Iannacone, M., Ciaccio, M. F., Gat-Viks, I., Tonti, E., DeGrace, M. M., Clauser, K. R., Garber, M., Eisenhaure, T. M., Yosef, N., Robinson, J., Sutton, A., Andersen, M. S., Root, D. E., von Andrian, U., Jones, R. B., ... Hacohen, N. (2011). Systematic discovery of TLR signaling components delineates viral-sensing circuits. Cell, 147(4), 853-867. https://doi.org/10.1016/j.cell.2011.10.022

@article{0455761d61f5415fb0103bdfebb35232,

title = "Systematic discovery of TLR signaling components delineates viral-sensing circuits",

abstract = "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.",

author = "Nicolas Chevrier and Philipp Mertins and Artyomov, {Maxim N.} and Shalek, {Alex K.} and Matteo Iannacone and Ciaccio, {Mark F.} and Irit Gat-Viks and Elena Tonti and DeGrace, {Marciela M.} and Clauser, {Karl R.} and Manuel Garber and Eisenhaure, {Thomas M.} and Nir Yosef and Jacob Robinson and Amy Sutton and Andersen, {Mette S.} and Root, {David E.} and {von Andrian}, Ulrich and Jones, {Richard B.} and Hongkun Park and Carr, {Steven A.} and Aviv Regev and Ido Amit and Nir Hacohen",

note = "Funding Information: We thank the members of the Hacohen and Regev laboratories, O. Takeuchi, B. Beutler, D. Mathis, P. Anderson, L. Glimcher, and D. Bartel for valuable discussions and comments; L. Gaffney and L. Solomon for assistance with figures and artwork; and S. Gupta and the Broad Genetic Analysis Platform for microarray processing. This work was supported by NIH grant U54 AI057159, the NIH New Innovator Award DP2 OD002230 (N.H.), and NIH P50 HG006193 (A.R., N.H.); a Ph.D fellowship from the Boehringer Ingelheim Fonds (N.C.); the Human Frontier Science Program Organization and a Claire and Emanuel G. Rosenblatt Award from the American Physicians Fellowship for Medicine in Israel (I.A.); NIH Pioneer Awards (A.R., H.P.); and a Career Award at the Scientific Interface from the Burroughs Wellcome Fund, the Sloan Foundation, and HHMI (A.R.). A.R. is an investigator of the Merkin Foundation for Stem Cell Research at the Broad Institute. This work was partially supported by a pilot award from the NIH Chicago Center for Systems Biology P50 GM081892-03 to R.B.J. and an award from the American Cancer Society Illinois Division to R.B.J.",

year = "2011",

month = nov,

day = "11",

doi = "https://doi.org/10.1016/j.cell.2011.10.022",

language = "الإنجليزيّة",

volume = "147",

pages = "853--867",

journal = "Cell",

issn = "0092-8674",

publisher = "Elsevier B.V.",

number = "4",

}

Chevrier, N, Mertins, P, Artyomov, MN, Shalek, AK, Iannacone, M, Ciaccio, MF, Gat-Viks, I, Tonti, E, DeGrace, MM, Clauser, KR, Garber, M, Eisenhaure, TM, Yosef, N, Robinson, J, Sutton, A, Andersen, MS, Root, DE, von Andrian, U, Jones, RB, Park, H, Carr, SA, Regev, A, Amit, I & Hacohen, N 2011, 'Systematic discovery of TLR signaling components delineates viral-sensing circuits', Cell, vol. 147, no. 4, pp. 853-867. https://doi.org/10.1016/j.cell.2011.10.022

TY - JOUR

T1 - Systematic discovery of TLR signaling components delineates viral-sensing circuits

AU - Chevrier, Nicolas

AU - Mertins, Philipp

AU - Artyomov, Maxim N.

AU - Shalek, Alex K.

AU - Iannacone, Matteo

AU - Ciaccio, Mark F.

AU - Gat-Viks, Irit

AU - Tonti, Elena

AU - DeGrace, Marciela M.

AU - Clauser, Karl R.

AU - Garber, Manuel

AU - Eisenhaure, Thomas M.

AU - Yosef, Nir

AU - Robinson, Jacob

AU - Sutton, Amy

AU - Andersen, Mette S.

AU - Root, David E.

AU - von Andrian, Ulrich

AU - Jones, Richard B.

AU - Park, Hongkun

AU - Carr, Steven A.

AU - Regev, Aviv

AU - Amit, Ido

AU - Hacohen, Nir

N1 - Funding Information: We thank the members of the Hacohen and Regev laboratories, O. Takeuchi, B. Beutler, D. Mathis, P. Anderson, L. Glimcher, and D. Bartel for valuable discussions and comments; L. Gaffney and L. Solomon for assistance with figures and artwork; and S. Gupta and the Broad Genetic Analysis Platform for microarray processing. This work was supported by NIH grant U54 AI057159, the NIH New Innovator Award DP2 OD002230 (N.H.), and NIH P50 HG006193 (A.R., N.H.); a Ph.D fellowship from the Boehringer Ingelheim Fonds (N.C.); the Human Frontier Science Program Organization and a Claire and Emanuel G. Rosenblatt Award from the American Physicians Fellowship for Medicine in Israel (I.A.); NIH Pioneer Awards (A.R., H.P.); and a Career Award at the Scientific Interface from the Burroughs Wellcome Fund, the Sloan Foundation, and HHMI (A.R.). A.R. is an investigator of the Merkin Foundation for Stem Cell Research at the Broad Institute. This work was partially supported by a pilot award from the NIH Chicago Center for Systems Biology P50 GM081892-03 to R.B.J. and an award from the American Cancer Society Illinois Division to R.B.J.

PY - 2011/11/11

Y1 - 2011/11/11

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=81055129618&partnerID=8YFLogxK

U2 - https://doi.org/10.1016/j.cell.2011.10.022

DO - https://doi.org/10.1016/j.cell.2011.10.022

M3 - مقالة

C2 - 22078882

SN - 0092-8674

VL - 147

SP - 853

EP - 867

JO - Cell

JF - Cell

IS - 4

ER -

Systematic discovery of TLR signaling components delineates viral-sensing circuits

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