title: Distinct single-cell signaling characteristics are conferred by the MyD88 and TRIF pathways during TLR4 activation.
abstract: Toll-like receptors (TLRs) recognize specific pathogen-associated molecular patterns and initiate innate immune responses through signaling pathways that depend on the adaptor proteins MyD88 (myeloid differentiation marker 88) or TRIF (TIR domain-containing adaptor protein-inducing interferon-β). TLR4, in particular, uses both adaptor proteins to activate the transcription factor nuclear factor κB (NF-κB); however, the specificity and redundancy of these two pathways remain to be elucidated. We developed a mathematical model to show how each pathway encodes distinct dynamical features of NF-κB activity and makes distinct contributions to the high variability observed in single-cell measurements. The assembly of a macromolecular signaling platform around MyD88 associated with receptors at the cell surface determined the timing of initial responses to generate a reliable, digital NF-κB signal. In contrast, ligand-induced receptor internalization into endosomes produced noisy, delayed, yet sustained NF-κB signals through TRIF. With iterative mathematical model development, we predicted the molecular mechanisms by which the MyD88- and TRIF-mediated pathways provide ligand concentration-dependent signaling dynamics that transmit information about the pathogen threat.
authors.affiliation: Institute for Quantitative and Computational Biosciences and Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90025, USA. San Diego Center for Systems Biology and Department of Chemistry and Biochemistry, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
authors.forename: Zhang
authors.initials: Z
authors.lastname: Cheng
authors.affiliation: Institute for Quantitative and Computational Biosciences and Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90025, USA. San Diego Center for Systems Biology and Department of Chemistry and Biochemistry, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
authors.forename: Brooks
authors.initials: B
authors.lastname: Taylor
authors.affiliation: San Diego Center for Systems Biology and Department of Chemistry and Biochemistry, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
authors.forename: Diana R
authors.initials: DR
authors.lastname: Ourthiague
authors.affiliation: Institute for Quantitative and Computational Biosciences and Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90025, USA. San Diego Center for Systems Biology and Department of Chemistry and Biochemistry, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA. ahoffmann@ucla.edu.
authors.forename: Alexander
authors.initials: A
authors.lastname: Hoffmann
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000378:metabolism*; D000465:Algorithms; D000818:Animals; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D002478:Cells, Cultured; D005269:Femur / Q000473:pathology; D007113:Immunity, Innate; D008024:Ligands; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008962:Models, Theoretical; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism*; D052002:NF-kappa B p50 Subunit; D015398:Signal Transduction / Q000502:physiology*; D051197:Toll-Like Receptor 4 / Q000378:metabolism*
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D008024:Ligands; D053594:Myeloid Differentiation Factor 88; D052002:NF-kappa B p50 Subunit; D051197:Toll-Like Receptor 4; C507780:Myd88 protein, mouse; C476286:Ticam1 protein, mouse; C493487:Tlr4 protein, mouse; C073701:Nfkb1 protein, mouse