| IFNAR2 forms, together with IFNAR1, the heterodimeric receptor complex that binds all type I interferon subtypes, including the various IFN-alpha species and IFN-beta, and functions as the higher-affinity binding subunit of the two, engaging ligand before IFNAR1 is recruited into the ternary signaling complex. The intracellular domain of IFNAR2 constitutively associates with the Janus kinase JAK1, distinguishing it from IFNAR1, whose intracellular domain instead associates with the related kinase TYK2, so that ligand-induced dimerization of the two receptor chains brings JAK1 and TYK2 into proximity and triggers their cross-phosphorylation and activation. Once activated, these kinases phosphorylate tyrosine residues within the intracellular domains of both receptor chains and directly phosphorylate the transcription factors STAT1 and STAT2, but the two receptor chains are not functionally interchangeable in this process: successive truncations of the IFNAR2 intracellular domain proportionally reduce constitutive STAT binding, STAT phosphorylation, and downstream target gene activation, whereas for IFNAR1 only the TYK2-binding site within its intracellular domain is required for signaling to proceed. STAT2 binds IFNAR2 through a constitutive, phosphorylation-independent docking site rather than through classical SH2 domain-phosphotyrosine recognition, and STAT1 is subsequently recruited into the complex through its interaction with STAT2 rather than by binding IFNAR2 directly, establishing IFNAR2 as the principal STAT-recruiting platform of the receptor pair even though TYK2 bound to IFNAR1 is required to initiate the kinase cascade. Tyrosine phosphorylation of IFNAR2 itself enhances downstream signaling, a modification proposed to promote dissociation of activated STAT proteins from the receptor once they have been phosphorylated, coupling receptor-level modification to STAT protein turnover within the signaling complex. Following STAT1 and STAT2 phosphorylation, the two transcription factors dimerize and associate with IRF9 to form the ISGF3 complex, which translocates to the nucleus and binds interferon-stimulated response elements to drive transcription of interferon-stimulated genes responsible for antiviral defense. IFNAR2 homodimers, unlike IFNAR1 homodimers, are sufficient on their own to induce STAT1/2-mediated signal transduction, directly demonstrating that IFNAR2 carries the dominant signal-initiating capacity within the receptor pair. Loss-of-function variants affecting IFNAR2 impair type I interferon responsiveness and are associated with severe susceptibility to viral infection. |
