IFNAR2 (interferon alpha and beta receptor subunit 2) is a critical component of the type I interferon receptor complex that initiates antiviral immune responses. IFNAR2 forms a heterodimeric receptor with IFNAR1, with the intracellular domain of IFNAR2 associating with JAK1 kinase 1. Upon type I interferon binding, IFNAR2 undergoes ligand-induced conformational changes that enable cross-phosphorylation of JAK1 and TYK2, which then phosphorylate STAT transcription factors 12. The intracellular domain of IFNAR2 contains multiple non-successive tyrosine residues and STAT binding sites that are essential for signal transduction and maintaining high signaling flux 1. Notably, alternative splicing generates a transposon-derived IFNAR2 isoform that functions as a potent decoy receptor, inhibiting interferon signaling across most tissues 3. IFNAR2 dysfunction has critical disease relevance: genetic variants reducing IFNAR2 expression are associated with severe COVID-19 4, and age-related post-translational modifications impairing STAT1-IFNAR2 interaction diminish antiviral defense in elderly individuals 5. Therapeutically, blocking IFNAR2 signaling with antibodies attenuates hyperinflammatory responses in chr21 SARS-CoV-2 infection 6. Mutations in IFNAR2 cause Immunodeficiency 45, highlighting its essential role in type I interferon-mediated antiviral defense.