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IFNAR1

Function

Together with IFNAR2, forms the heterodimeric receptor for type I interferons (including interferons alpha, beta, epsilon, omega and kappa) (PubMed:10049744, PubMed:14532120, PubMed:15337770, PubMed:2153461, PubMed:21854986, PubMed:24075985, PubMed:31270247, PubMed:33252644, PubMed:35442418, PubMed:7813427). Type I interferon binding activates the JAK-STAT signaling cascade, resulting in transcriptional activation or repression of interferon-regulated genes that encode the effectors of the interferon response (PubMed:10049744, PubMed:21854986, PubMed:7665574). Mechanistically, type I interferon-binding brings the IFNAR1 and IFNAR2 subunits into close proximity with one another, driving their associated Janus kinases (JAKs) (TYK2 bound to IFNAR1 and JAK1 bound to IFNAR2) to cross-phosphorylate one another (PubMed:21854986, PubMed:32972995, PubMed:7665574, PubMed:7813427). The activated kinases phosphorylate specific tyrosine residues on the intracellular domains of IFNAR1 and IFNAR2, forming docking sites for the STAT transcription factors (PubMed:21854986, PubMed:32972995, PubMed:7526154, PubMed:7665574, PubMed:7813427). STAT proteins are then phosphorylated by the JAKs, promoting their translocation into the nucleus to regulate expression of interferon-regulated genes (PubMed:19561067, PubMed:21854986, PubMed:32972995, PubMed:7665574, PubMed:7813427, PubMed:9121453). Can also act independently of IFNAR2: form an active IFNB1 receptor by itself and activate a signaling cascade that does not involve activation of the JAK-STAT pathway (By similarity).

Involvement in disease

Immunodeficiency 106, susceptibility to viral infections

IMD106

An autosomal recessive immunologic disorder characterized by increased susceptibility to viral infections beginning in infancy or early childhood. IMD106 affected individuals may demonstrate adverse reactions to vaccination with live attenuated viral vaccines, most notably measles, mumps and rubella (MMR) and yellow fever vaccines. A subset of IMD106 patients develop severe reactions, including excessive hyperinflammatory response, encephalopathy, acute respiratory distress syndrome, and multiorgan failure. IMD106 may also predispose to severe respiratory infection with SARS-CoV-2.

None

Disease susceptibility is associated with variants affecting the gene represented in this entry.

Post-translational modifications

Ubiquitinated, leading to its internalization and degradation (PubMed:14532120, PubMed:15337770). Polyubiquitinated via 'Lys-48'-linked and 'Lys-63'-linked ubiquitin chains, leading to receptor internalization and lysosomal degradation (PubMed:18056411). The 'Lys-63'-linked ubiquitin chains are cleaved off by the BRISC complex (PubMed:24075985).

Phosphorylated on tyrosine residues in response to interferon-binding: phosphorylation by TYK2 tyrosine kinase creates docking sites for STAT proteins (PubMed:10049744, PubMed:7526154). Phosphorylated on serine residues in response to interferon binding; this promotes interaction with FBXW11 and ubiquitination (PubMed:14532120, PubMed:15337770, PubMed:24075985).

Palmitoylation at Cys-463 is required for the activation of STAT1 and STAT2.

Sequence Similarities

Belongs to the type II cytokine receptor family.

Tissue Specificity

IFN receptors are present in all tissues and even on the surface of most IFN-resistant cells. Isoform 1, isoform 2 and isoform 3 are expressed in the IFN-alpha sensitive myeloma cell line U266B1. Isoform 2 and isoform 3 are expressed in the IFN-alpha resistant myeloma cell line U266R. Isoform 1 is not expressed in IFN-alpha resistant myeloma cell line U266R.

Cellular localization

Alternative names

IFNAR, IFNAR1, Interferon alpha/beta receptor 1, IFN-R-1, IFN-alpha/beta receptor 1, Cytokine receptor class-II member 1, Cytokine receptor family 2 member 1, Type I interferon receptor 1, CRF2-1

swissprot:P17181 omim:107450 entrezGene:3454

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