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Systematic discovery of TLR signaling components delineates viral-sensing circuits

Item Type:Article
Title:Systematic discovery of TLR signaling components delineates viral-sensing circuits
Creators Name:Chevrier, N. and Mertins, P. and Artyomov, M.N. and Shalek, A.K. and Iannacone, M. and Ciaccio, M.F. and Gat-Viks, I. and Tonti, E. and DeGrace, M.M. and Clauser, K.R. and Garber, M. and Eisenhaure, T.M. and Yosef, N. and Robinson, J. and Sutton, A. and Andersen, M.S. and Root, D.E. and von Andrian, U. and Jones, R.B. and Park, H. and Carr, S.A. and Regev, A. and Amit, I. and Hacohen, N.
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.
Keywords:Dendritic Cells, Inbred C57BL Mice, Interferon Regulatory Factor-3, Interferons, Protein-Serine-Threonine Kinases, Signal Transduction, Toll-Like Receptors, Viruses, Animals, Mice
Publisher:Cell Press
Page Range:853-867
Date:10 November 2011
Official Publication:https://doi.org/10.1016/j.cell.2011.10.022
PubMed:View item in PubMed

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