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 journalArticle

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 languageEnglish
Pages (from-to)853-867
Number of pages15
JournalCell
Volume147
Issue number4
DOIs
Publication statusPublished - Nov 11 2011

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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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