Down-modulation of type 1 interferon responses by receptor cross-competition for a shared Jak kinase.
In contrast to the large number of class I and II cytokine receptors, only four Janus kinase (Jak) proteins are expressed in mammalian cells, implying the shared use of these kinases by many different receptor complexes. Consequently, if receptor numbers exceed the amount of available Jak, cross-interference patterns can be expected. We have engineered two model cellular systems expressing two different exogenous Tyk2-interacting receptors. A receptor chimera was generated wherein the extracellular part of the interferon type 1 receptor (Ifnar1) component of the interferon-alpha/beta receptor is replaced by the equivalent domain of the erythropoietin receptor. Despite Tyk2 activation, erythropoietin treatment of cells expressing this erythropoietin receptor/Ifnar1 chimera did not evoke any detectable IFN-type response. However, a dose-dependent interference with signal transduction via the endogenous Ifnar complex was found for STAT1, STAT2, STAT3, Tyk2, and Jak1 activation, for gene induction, and for antiviral activity. In a similar approach, cells expressing the beta1 chain of the interleukin-12 receptor showed a reduced transcriptional response to IFN-alpha as well as reduced STAT and kinase activation. In both model systems, titration of the Tyk2 kinase away from the Ifnar1 receptor chain accounts for the observed cross-interference.
Dondi
E
E
Laboratoire de Signalisation des Cytokines, Institut Pasteur, 25, rue du Dr. Roux, 75724 Paris, cedex 15 France.
Pattyn
E
E
Lutfalla
G
G
Van Ostade
X
X
Uzé
G
G
Pellegrini
S
S
Tavernier
J
J
D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D002469:Cell Separation; D002470:Cell Survival; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D004789:Enzyme Activation; D005434:Flow Cytometry; D006801:Humans; D016898:Interferon-alpha / Q000378:metabolism; D016899:Interferon-beta / Q000378:metabolism; D053613:Janus Kinase 1; D007700:Kinetics; D008024:Ligands; D008156:Luciferases / Q000378:metabolism; D008565:Membrane Proteins; D010766:Phosphorylation; D010957:Plasmids / Q000378:metabolism; D011233:Precipitin Tests; D011485:Protein Binding; D014176:Protein Biosynthesis; D017434:Protein Structure, Tertiary; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D011506:Proteins / Q000378:metabolism*; D053633:Receptor, Interferon alpha-beta; D017467:Receptors, Erythropoietin / Q000378:metabolism; D017471:Receptors, Interferon / Q000378:metabolism; D018123:Receptors, Interleukin / Q000378:metabolism; D053707:Receptors, Interleukin-12; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D053634:TYK2 Kinase; D014158:Transcription, Genetic; D014162:Transfection; D014443:Tyrosine / Q000378:metabolism
C507964:IFNAR1 protein, human; C508438:IL12RB1 protein, human; D016898:Interferon-alpha; D008024:Ligands; D008565:Membrane Proteins; D011506:Proteins; D017467:Receptors, Erythropoietin; D017471:Receptors, Interferon; D018123:Receptors, Interleukin; D053707:Receptors, Interleukin-12; D053633:Receptor, Interferon alpha-beta; D014443:Tyrosine; D016899:Interferon-beta; D008156:Luciferases; D011505:Protein-Tyrosine Kinases; C507904:JAK1 protein, human; D053613:Janus Kinase 1; D053634:TYK2 Kinase; C070139:TYK2 protein, human