| First Author | Cheng Z | Year | 2015 |
| Journal | Sci Signal | Volume | 8 |
| Issue | 385 | Pages | ra69 |
| PubMed ID | 26175492 | Mgi Jnum | J:260285 |
| Mgi Id | MGI:6140629 | Doi | 10.1126/scisignal.aaa5208 |
| Citation | Cheng Z, et al. (2015) Distinct single-cell signaling characteristics are conferred by the MyD88 and TRIF pathways during TLR4 activation. Sci Signal 8(385):ra69 |
| abstractText | 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 kappaB (NF-kappaB); 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-kappaB 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-kappaB signal. In contrast, ligand-induced receptor internalization into endosomes produced noisy, delayed, yet sustained NF-kappaB 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. |
