The molecular basis for differential type I interferon signaling

Abstract

Type I interferons (IFN-1) are cytokines that affect the expression of thousands of genes, resulting in profound cellular changes. IFN-1 activates the cell by dimerizing its two-receptor chains, IFNAR1 and IFNAR2, which are expressed on all nucleated cells. Despite a similar mode of binding, the different IFN-1s activate a spectrum of activities. The causes for differential activation may stem from differences in IFN-1-binding affinity, duration of binding, number of surface receptors, induction of feedbacks, and cell type-specific variations. All together these will alter the signal that is transmitted from the extracellular domain inward. The intracellular domain binds, directly or indirectly, different effector proteins that transmit signals. The composition of effector molecules deviates between different cell types and tissues, inserting an additional level of complexity to the system. Moreover, IFN-1s do not act on their own, and clearly there is much cross-talk between the activated effector molecules by IFN-1 and other cytokines. The outcome generated by all of these factors (processing step) is an observed phenotype, which can be the transformation of the cell to an antiviral state, differentiation of the cell to a specific immune cell, senescence, apoptosis, and many more. IFN-1 activities can be divided into robust and tunable. Antiviral activity, which is stimulated by minute amounts of IFN-1 and is common to all cells, is termed robust. The other activities, which we term tunable, are cell type-specific and often require more stringent modes of activation. In this review, I summarize the current knowledge on the mode of activation and processing that is initiated by IFN-1, in perspective of the resulting phenotypes.

Type I interferons act directly on nociceptors to produce pain sensitization: Implications for viral infection-induced pain

“…We generated tSNE plots to show genes expression in specific clusters of cells (van der Maaten and Hinton, 2008). IFN-α and IFN-β bind a heterodimeric transmembrane receptor termed the IFN-α receptor (IFNAR), which is composed of IFNAR1 and IFNAR2 subunits (Schreiber, 2017). We observed expression of both Ifnar1 (Interferon receptor 1, IFNR1) and Ifnar2 (Interferon receptor 2, IFNR2) mRNAs with the neuronal marker rbfox3 (NeuN), indicating their presence in neuronal populations in the mouse DRG (Figure 2A).…”

“…From this perspective, an ideal candidate is type I interferons (IFNs) because these cytokines are rapidly induced in a wide variety of cells upon exposure to virus. These IFNs then act via their cognate receptors to induce signaling in target cells (Schreiber, 2017; Barrat et al, 2019). We hypothesized that type I IFNs might act directly on peripheral nociceptors to cause pain.…”

Hepatitis B virus sensitivity to interferon‐α in hepatocytes is more associated with cellular interferon response than with viral genotype

“…B,C and http://onlinelibrary.wiley.com/doi/10.1002/hep.29609/suppinfo). Considering that the actions of IFN‐α are closely associated with the cell‐surface receptor concentrations and a much higher number of IFNAR receptors is associated with antiproliferative, rather than antiviral, activity, we further examined the expression of IFNAR1, IFNAR2, TYK2, and JAK1. The results showed that these signaling molecules were expressed highly in HepG2‐NTCP, but at a much lower level in PHH (Fig D), which might contribute to the differential induction pattern of ISGs and antiviral effects.…”

Expression Density of Receptors as a Potent Regulator of Cell Function and Property in Health and Pathology

“…Of note, both the high expression of conventional EGFR and its phosphorylated form (pEGFR) can be unfavorable prognostic factors for cancer patients. The hyperexpression of pEGFR on salivary gland tumor cells enhanced their migratory activity and promoted lymphogenic metastases and invasion into the lymph nodes [26]. …”