Interferon-alpha/beta receptor

The interferon-α/β receptor (IFNAR) is a virtually ubiquitous membrane receptor which binds endogenous type I interferon (IFN) cytokines. Endogenous human type I IFNs include many subtypes, such as interferons-α, -β, -ε, -κ, -ω, and -ζ. Activation of various innate immune signaling pathways (TLR3, TLR4, TLR7, TLR8, TLR9, cGAS, RIG-I, MDA-5) leads to the rapid induction of type I IFNs due to their (mostly) intronless gene structure. The regulatory elements upstream of type I IFN genes differ, allowing differential transcription of type I IFNs in response to stimuli. In particular, IFNβ contains a κB regulatory site, whereas IFNα subtypes do not. Production of specific type I IFNs is usually limited to a small number of type I IFN subtypes. Once secreted, type I IFNs signal through IFNAR in a paracrine and autocrine manner. IFNAR is a heteromeric cell surface receptor composed of two subunits, referred to as the low affinity subunit, IFNAR1, and the high affinity subunit, IFNAR2. Upon binding of type I interferons, IFNAR activates the JAK-STAT signalling pathway, along with MAPK, PI3K, and Akt signaling pathways. IFNAR agonism results in transcriptional changes, with the potential to increase or suppress the transcription of over 2000 different genes. For example, type I IFNs induce interferon-stimulated gene (ISG) expression, classically resulting in a robust anti-viral immune response. Additionally, IFNs largely impact cell health and viability, with effects on apoptosis, autophagy, cell differentiation, and proliferation. The diverse effects of type I IFNs is likely dependent on the cellular and environmental context. Different responses, e.g. antiviral versus antiproliferative responses, to type I IFNs subtypes have been studied and proximal signaling, such as STAT phosphorylation, does not appear to correlate with the outcome. Furthermore, while differential effects manifest after several days of chronic stimulation, changes to receptor structure, orientation, or stoichiometry have not elucidated the cause for differential signaling via different type I IFN subtypes. Current hypotheses for differential signaling include ligand-specific differences to the stability, or lifetime, of the ternary complex, ligand-induced changes to internalization and trafficking of the receptor and currently unappreciated differences to ligand-receptor structure. Type I IFN receptor forms a ternary complex, composed of its two subunits IFNAR1 and IFNAR2, and a type I IFN ligand. Ligand binding to either subunit is required for and precedes dimerization and activation of the receptor. Each subunit of IFNAR contains an N-terminal ligand binding domain (with two or four fibronectin type II-like subdomains, for IFNAR2 and IFNAR1, respectively), a transmembrane (TM) domain, and a cytoplasmic domain. Each type I IFN ligand contains a 'hotspot', or a sequence of conserved amino acids that are involved in binding to the receptor, specifically the high affinity receptor IFNAR2, which determines the affinity of each ligand for the receptor. Structural analysis of type I IFN receptor with different type I IFN ligand subtypes revealed a similar binding site for the different agonists. Mutagenesis studies of type I IFNs, IFNAR1 and IFNAR2 demonstrated important binding residues, i.e. 'hotspots', on the type I IFN subtypes which influenced its ability to bind to IFNAR2. Type I IFN binding to IFNAR1 was less strongly impacted by mutating single amino acids to alanine. Importantly, structural studies have not revealed differences in ternary complex structures with IFNAR and various type I IFN subtypes, despite differences in ligand affinities. The evolutionary conservation of type I IFN subtypes binding the same IFNAR receptor at the same site with differing affinities suggests that type I IFNs are nonredundant and potentially regulate different cellular responses. Efforts to engineer a more potent IFNα2 elicited a cellular response similar to IFNβ, suggesting that the affinity of type I IFNs for IFNAR has an important role in regulating the downstream response. Human IFNAR1 and IFNAR2 genes are located on chromosome 21q22.1. IFNAR1 is the low affinity subunit, originally cloned in 1990, and is composed of four fibronectin type II-like (FNII-like) subdomains, termed SD1-4. Type I IFNs bind SD1-3 with a typical binding affinity between 0.5–5μM; IFNα1 and IFNβ are exceptions with binding affinities of 220nM and 100nM, respectively. Type I IFNs have a binding association rate of 5x105M/s with a variable dissociation rate that determines type I IFN subtype affinity for IFNAR1.