Systematic Discovery of TLR Signaling Components Delineates Viral-Sensing Circuits

SummaryDeciphering 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.

Graphical AbstractFigure optionsDownload full-size imageDownload high-quality image (326 K)Download as PowerPoint slideHighlights► Integrative strategy for dissecting mammalian signaling networks ► Strategy identifies factors and pathways controlling TLR signals ► Polo-like kinases are key regulators of well-established IFN-inducing pathways ► The kinases activate a signaling branch involving a dozen proteins