Abstract
The Type I Interferon family of cytokines all act through the same cell surface receptor and induce phosphorylation of the same subset of response regulators of the STAT family. Despite their shared receptor, different Type I Interferons have different functions during immune response to infection. In particular, they differ in the potency of their induced anti-viral and anti-proliferative responses in target cells. It remains not fully understood how these functional differences can arise in a ligand-specific manner both at the level of STAT phosphorylation and the downstream function. We use a minimal computational model of Type I Interferon signaling, focusing on Interferon-α and Interferon-β. We validate the model with quantitative experimental data to identify the key determinants of specificity and functional plasticity in Type I Interferon signaling. We investigate different mechanisms of signal discrimination, and how multiple system components such as binding affinity, receptor expression levels and their variability, receptor internalization, short-term negative feedback by SOCS1 protein, and differential receptor expression play together to ensure ligand specificity on the level of STAT phosphorylation. Based on these results, we propose phenomenological functional mappings from STAT activation to downstream anti-viral and anti-proliferative activity to investigate differential signal processing steps downstream of STAT phosphorylation. We find that the negative feedback by the protein USP18, which enhances differences in signaling between Interferons via ligand-dependent refractoriness, can give rise to functional plasticity in Interferon-α and Interferon-β signaling, and explore other factors that control functional plasticity. Beyond Type I Interferon signaling, our results have a broad applicability to questions of signaling specificity and functional plasticity in signaling systems with multiple ligands acting through a bottleneck of a small number of shared receptors.
Highlights
Specificity in molecular signaling networks is essential for cells to respond appropriately to changes in their environment
Further model validation is provided by looking at the effect of two mutations to IFNa2 on the pSTAT dose-response curve
This functional plasticity arises from a combination of biophysical and dynamic factors and is at least partially decoupled from ligand concentration, indicating the presence of absolute discrimination in this signaling system [29, 38,39,40]
Summary
Specificity in molecular signaling networks is essential for cells to respond appropriately to changes in their environment. Overlapping components between signal pathways is known as crosstalk, and this feature has been observed in cytokine signaling through the Jak/STAT pathway, the TGF superfamily of ligands acting through the SMAD pathway, a variety of ligands acting through the NF-kB pathway, and others [3,4,5,6,7,8] These examples challenge the idea of specificity based purely on ligand-receptor binding pairs because the same level of receptor occupancy can be achieved by either a low concentration of a high affinity ligand or by a high concentration of a low affinity ligand [9]. Crosstalk without distinct cellular responses generates redundancy between ligands, which may be useful for other reasons [12]
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