期刊
SCIENCE SIGNALING
卷 8, 期 385, 页码 -出版社
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/scisignal.aaa5208
关键词
-
资金
- NIH [R01 GM071573, R01 CA141722]
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-beta). TLR4, in particular, uses both adaptor proteins to activate the transcription factor nuclear factor kappa B (NF-kappa B); 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-kappa B 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-kappa B signal. In contrast, ligand-induced receptor internalization into endosomes produced noisy, delayed, yet sustained NF-kappa B 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.
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