IFNA2: The prototypic human alpha interferon

Abstract

The human interferon α2 (IFNα2) was the first highly active IFN subtype to be cloned in the early eighties. It was also the first IFN and the first cytokine to be produced and commercialized by the pharmaceutical industry. Ipso facto it became the favorite IFNα subtype for academic researchers. For this fortunate reason IFNα2 has been at the origin of most discoveries related to the mechanism of action of type I interferons.

Keywords: Cytokine; Interferon α2; Type I interferon.

Figure 1. Induction of type I-IFNs

Damage and pathogen associated molecular patterns are recognized by cytosolic sensors and/or endosomal receptors which activate several pathways leading to the activation of IRF kinases and the subsequent phosporylation of IRF3 and IRF7.Once phosphorylated, these IRF translocate into the nucleus, bind to the promoter of type I IFN genes and activate their transcription. Unlike IFNB gene, IFNA2 gene requires both IRF3 and IRF7 activation to be induced. cGAS: Cyclic GMP-AMP synthase; CpG DNA: DNA with cytidine-phosphate-guanosine motifs; DAI: DNA-dependent activator of IFNregulatory factors; dsRNA: double strand RNA; IKK: inhibitor of kappaB kinase; IRAK: Interleukin-1 receptor-associated kinase; IRF: Interferon regulatory factors; MDA5: Melanoma Differentiation-Associated protein 5; MyD88: myeloid differentiation primary response protein 88; RIG-I: retinoic acid-inducible gene 1; STING: Stimulator of interferon genes; TBK: TANK-binding kinase; TLR: Toll-like receptor; TRIF: Toll/IL-1 receptor (TIR) domain-containing adaptor inducing IFNβ, TRAF: TNF receptor associated factors; VRE: virus responsive element.

Figure 2. Canonical JAK/STAT signalling pathway of type I-IFNs

Type I-IFN/IFNAR2/IFNAR1 ternary complex induces transphosphorylation of receptor associated JAK kinases which in turn phosphorylate specific tyrosine residues on IFNAR1 and IFNAR2. These phosphorylated tyrosine residues are docking sites for signal transducers and activators of transcription (STAT) which are then recruited to the receptor complex and phosporylated (pSTAT) on specific tyrosine residue. pSTAT2 and pSTAT1 heterodimerize to form together with IRF9 the ISGF3 complex which translocates into the nucleus and binds to IFN stimulated responsive elements (ISRE) in the regulatory region of IFN-stimulated genes (ISG)