Interferon receptor

The interferon receptor superfamily Cytokine receptor type II family Receptors for IFN-cx, -P, -y, IL-10... 

Studies have actually revealed two type I interferon receptor polypeptides. Sequence data from cloning studies place both in the class II cytokine receptor family. Both are transmembrane N-linked glycoproteins. Studies using isolated forms of each show that one polypeptide (called the a/p receptor) is capable of binding all type I interferons. The other one (the ap receptor) is specific for IFN-a-B (a specific member of the IFN-a family). Both receptors are present on most cell types. 

Roisman LC, Piehler J, Trosset JY et al (2001) Structure of the interferon-receptor complex determined by distance constraints from double-mutant cycles and flexible docking. Proc Natl Acad Sci U S A 98 13231-13236... 

Interferons are cellular glycoproteins produced by the host cells which exert complex antiviral, immunoregulatory and antiproliferative activities. After binding to interferon receptors it acts through cellular metabolic processes which involves synthesis of viral RNA and proteins. Interferon receptors are tyrosine protein kinase receptors which on activation phosphorylate cellular proteins. These then induce transcription of interferon induced proteins which exert antiviral effects. There are three type of interferons - alpha, beta and gamma. 

Fig. 11.2. Domain structure of cytokine receptors. Schematic representation of the domain structure of selected cytokine receptors. WS motif conserved WSXWS sequence (W tryptophan S serine X non-conserved amino add) IL interleukin EpoR receptor for erythropoietin GHR growth hormone receptor LIF-R leukemia inhibitory factor receptor G-CSFR granulocyte colony stimulating factor receptor IFNR interferon receptor TNFR tumor necrosis factor receptor NGFR nerve growth factor receptor Fas, CD40 transmembrane receptors of lymphocytes.

It is assumed that the Jak kinases bind to a cytoplasmic section of the receptor, which is in the vicinity of the membrane and contains two conserved sequence elements, Box 1 and Box 2. Binding of the Jak kinases leads to their activation, a process linked to mutual phosphorylation of the Jak kinases (Fig. 11.6). Activation of the Jak kinases may take place in a homodimeric receptor complex or it may also occm in hetero-oligomeric complexes. The circumstances are comphcated in that two (or more) Jak kinases may associate at an activated receptor. Two different Jak kinases are required for signal transduction via interferon receptors (see Fig. 11.8). Furthermore, the different Jak kinases are specific for the corresponding receptors. 

Abramovich, C, L.M. Shulman, E. Ratovitski, S. Harroch, M. Tovey, P. Eid, and M. Revel, Differential tyrosine phosphorylation of the IFNAR chain of the type I interferon receptor and of an associated surface protein in response to IFN-alpha and IFN-beta. Embo J, 1994. 13(24) 5871-7. 

Interferons. The interferons (IFNs),196,197 which were discovered in 1957, are proteins secreted by leukocytes, fibroblasts, and activated lymphocytes. They inhibit replication of viruses as well as the growth of host cells and also have antitumor activity. Interferons are classified as a (from leukocytes), (3 (from fibroblasts), and y (from lymphocytes). According to their affinities for the two types of known interferon receptors, interferons IFN-a, IFN-(3, and the less well known IFN-0) and IFN-t are... 

IL-22. IL-10-related T cell-derived inducible factor (IL-TIF provisionally designated IL-22) is a cytokine distantly related to IL-10 and is produced by activated T cells (D16). IL-22 receptor, a new member of the interferon receptor family, and CRF2-4, a member of the class II cytokine receptor family, join together to enable IL-22 signaling. Cell lines that respond to IL-22 by activation of STATs 1,3, and 5, but unresponsive to IL-10, have been identified (XI). In contrast to IL-10, IL-22 does not inhibit the LPS-induced production of proinflammatory cytokines by monocytes, but it has a modest inhibitory effect on IL-4 production from Th2 cells (XI). 

Bazan, J. F. (1990b). Shared architecture of hormone binding domains in type I and II interferon receptors. Cell, 753-754. 

Chill, J. H., Nivasch, R., Levy, R., Albeck, S., Schreiber, G., and Anglister, J. (2002). The human interferon receptor NMR-based modeling, mapping of the IFN-alpha 2 binding site, and observed ligand-induced tightening. Biochemistry 41, 3575-3585. 

Vileek, J., Aguet, M., and Reis, L. F. L. (1998). In Cytokine Knockouts (ed S. K. Durum and K. Muegge), Knockouts of interferons, interferon receptors and interferon signaling components, pp. 207-225. Humana Press, Totowa, NJ. 

Khine AA, Lingwood CA. Functional significance of globotriao-sylceramide in 2 interferon/ type I interferon receptor mediated... 

As previously mentioned, interferons are cytokines produced by cells to protect them from viral infection, and anti-interferon strategies are a part of the immune evasion repertoire of most viruses. These mechanisms include the production of soluble versions of interferon receptors, which act as decoys. These decoys bind and inactivate interferons before they reach their destination - normal, membrane-bound receptors.22... 

The g interferon receptor activates Jakl and Jak2 kinases through phosphorylation of their own tyrosine residues. 

Stimulation of the g and a interferon receptors leads to the activation of Jak kinase family members which phosphorylate a variety of STAT transcription factors. Regulation of interferon-responsive genes is the result of phosphorylation-dependent nuclear translocation and dimerization of STAT transcription factors, which is required to activate their DNA binding and transcriptional regulatory functions. 

Khine A.A., Lingwood C.A., Functional significance of globotriaosyl ceramide in interferon-alpha(2)/type 1 interferon receptor-mediated antiviral activity, Journal of Cellular Physiology 182 (2000) 97-108. 

---