Structural and dynamic determinants of type I interferon receptor assembly and their functional interpretation

Abstract

Summary Type I interferons (IFNs) form a network of homologous cytokines that bind to a shared, heterodimeric cell surface receptor and engage signaling pathways that activate innate and adaptive immune responses. The ability of IFNs to mediate differential responses through the same cell surface receptor has been subject of a controversial debate and has important medical implications. During the past decade, a comprehensive insight into the structure, energetics, and dynamics of IFN recognition by its two-receptor subunits, as well as detailed correlations with their functional properties on the level of signal activation, gene expression, and biological responses were obtained. All type I IFNs bind the two-receptor subunits at the same sites and form structurally very similar ternary complexes. Differential IFN activities were found to be determined by different lifetimes and ligand affinities toward the receptor subunits, which dictate assembly and dynamics of the signaling complex in the plasma membrane. We present a simple model, which explains differential IFN activities based on rapid endocytosis of signaling complexes and negative feedback mechanisms interfering with ternary complex assembly. More insight into signaling pathways as well as endosomal signaling and trafficking will be required for a comprehensive understanding, which will eventually lead to therapeutic applications of IFNs with increased efficacy.

Murine Oncostatin M Acts via Leukemia Inhibitory Factor Receptor to Phosphorylate Signal Transducer and Activator of Transcription 3 (STAT3) but Not STAT1, an Effect That Protects Bone Mass

“…These include not only LIFR and OSMR (1,74,75) but also type I interferons (76). In the case of mOSM, our data suggest that impaired gp130 and LIFR phosphorylation may be responsible for the bias toward STAT3 signaling, but how receptor phosphorylation level is controlled remains unknown.…”

Absolute Ligand Discrimination by Dimeric Signaling Receptors

“…2 is very different from that of the monomeric receptor, and is shown in Fig. 2 for typical values of the parameters (10,14,22). First, the number of ternary complexes is nonmonotonic in the ligand concentration and reaches a maximum T max at the concentration C Ã ¼ ffiffiffiffiffiffiffiffiffiffi ffi…”

“…A striking example is signaling of the Type I Interferon family in which 16 different Interferon subtypes bind to the same heterodimeric receptor but elicit distinct cellular responses (10,11). In less extreme cases, different ligands might share only one receptor subunit or maintain specificity on the receptor level but activate overlapping sets of downstream regulators (3,12,13).…”

“…Although it is clear that the discrimination at least partially relies on the differences in ligand binding affinity to the receptor (10)(11)(12)14), that alone is not always sufficient for distinguishing between different ligands. Indeed, in the classical view of (monomeric) receptor signaling, the receptor occupancy, which dictates the signaling strength, is…”

Cytokine Activation by Antibody Fragments Targeted to Cytokine-Receptor Signaling Complexes

“…In the interferon system, IFNAR2 is the high affinity receptor chain that exhibits ϳnM affinity for IFNs. The IFN low affinity receptor chain, IFNAR1, binds to the IFN-IFNAR2 binary complex with ϳM affinity to form the ternary IFN-IFNAR1-IFNAR2 signaling complex (17). IFN-induced ternary complex formation activates the JAK/STAT pathway and the expression interferon-stimulated genes (ISGs), which ultimately give rise to antiviral (AV), antiproliferative (AP), and immunomodulatory cellular responses (18).…”