Activity of hybrid type I interferons in cells lacking Tyk2: a common region of IFN-alpha 8 induces a response, but IFN-alpha2/8 hybrids can behave like IFN-beta.
Type I interferons (IFNs) are a family of pleiotropic cytokines with antiviral, antiproliferative, and immunomodulatory properties. The type I IFN family consists of 12 IFN-alpha subtypes, IFN-beta, and IFN-omega. Cells lacking the receptor-associated protein kinase Tyk2 (U1A) are responsive only to IFN-beta and partially to IFN-alpha8. We constructed a series of IFN-alpha2/alpha8 hybrids and mutants and identified the region within IFN-alpha8 responsible for its activity in Tyk2-deficient cells. The same domain mediates the interactions between IFN and IFN-alpha receptor (IFNAR) in Tyk2-complemented and Tyk2-deficient cells (U1A). The presence or absence of Tyk2 altered the inhibitory effects of anti-IFNAR antibodies, suggesting that the IFN-alpha binding domain on IFNAR is altered by the presence of Tyk2. The activity of IFN-beta was not significantly affected by the deletion of Tyk2, and, surprisingly, one of our IFN-alpha2/alpha8 hybrids (IFN-alpha288) behaved like IFN-beta in a number of assays that distinguish IFN-alphas from IFN-beta. This suggests that this hybrid mimics the interactions of IFN-beta with the receptor and also suggests the existence of a distinct binding site(s) on IFNAR for IFN-beta and some hybrid IFN-alphas.
Platis
Dimitris
D
Imperial College Faculty of Medicine at St. Mary's Hospital, London W2 1NY, England.
Foster
Graham R
GR
D000595:Amino Acid Sequence; D000906:Antibodies; D002478:Cells, Cultured; D006801:Humans; D016898:Interferon-alpha / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D016899:Interferon-beta / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D008969:Molecular Sequence Data; D009154:Mutation; D011505:Protein-Tyrosine Kinases / Q000172:deficiency / Q000235:genetics; D053633:Receptor, Interferon alpha-beta; D017471:Receptors, Interferon / Q000276:immunology / Q000378:metabolism*; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction; D013329:Structure-Activity Relationship; D053634:TYK2 Kinase
D000906:Antibodies; D016898:Interferon-alpha; D017471:Receptors, Interferon; D053633:Receptor, Interferon alpha-beta; D016899:Interferon-beta; D011505:Protein-Tyrosine Kinases; D053634:TYK2 Kinase; C070139:TYK2 protein, human