1. Systematic Discovery of TLR Signaling Components Delineates Viral-Sensing Circuits
- Author
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Nir Yosef, Mark F. Ciaccio, Thomas Eisenhaure, Marciela M. DeGrace, Philipp Mertins, Richard Bradley Jones, Matteo Iannacone, Elena Tonti, Irit Gat-Viks, Hongkun Park, Ido Amit, Steven A. Carr, Jacob T. Robinson, Manuel Garber, Mette S. Andersen, Alex K. Shalek, Nicolas Chevrier, David E. Root, Maxim N. Artyomov, Amy Sutton, Ulrich H. von Andrian, Karl R. Clauser, Nir Hacohen, Aviv Regev, 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, M, Root, De, von Andrian, U, Jones, Rb, Park, H, Carr, Sa, Regev, A, Amit, I, and Hacohen, N
- Subjects
Disease ,Computational biology ,Protein Serine-Threonine Kinases ,Biology ,Article ,General Biochemistry, Genetics and Molecular Biology ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,In vivo ,Animals ,Humans ,Receptor ,Gene ,030304 developmental biology ,0303 health sciences ,Biochemistry, Genetics and Molecular Biology(all) ,Kinase ,Toll-Like Receptors ,ComputingMilieux_PERSONALCOMPUTING ,Phosphoproteomics ,Dendritic Cells ,Cell biology ,Mice, Inbred C57BL ,030220 oncology & carcinogenesis ,Viruses ,Female ,Interferon Regulatory Factor-3 ,Interferons ,Signal transduction ,Signal Transduction - Abstract
SUMMARY 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.
- Published
- 2011