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 - 10.1016/j.cell.2011.10.022
DO - 10.1016/j.cell.2011.10.022
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C2 - 22078882
AN - SCOPUS:81055129618
SN - 0092-8674
VL - 147
SP - 853
EP - 867
JO - Cell
JF - Cell
IS - 4
ER -