Role of the interleukin (IL)-28 receptor tyrosine residues for antiviral and antiproliferative activity of IL-29/interferon-lambda 1: similarities with type I interferon signaling.
Interferon (IFN)-lambda 1, -lambda 2, and -lambda 3 are the latest members of the class II cytokine family and were shown to have antiviral activity. Their receptor is composed of two chains, interleukin-28R/likely interleukin or cytokine or receptor 2 (IL-28R/LICR2) and IL-10R beta, and mediates the tyrosine phosphorylation of STAT1, STAT2, STAT3, and STAT5. Here, we show that activation of this receptor by IFN-lambda 1 can also inhibit cell proliferation and induce STAT4 phosphorylation, further extending functional similarities with type I IFNs. We used IL-28R/LICR2-mutated receptors to identify the tyrosines required for STAT activation, as well as antiproliferative and antiviral activities. We found that IFN-lambda 1-induced STAT2 tyrosine phosphorylation is mediated through tyrosines 343 and 517 of the receptor, which showed some similarities with tyrosines from type I IFN receptors involved in STAT2 activation. These two tyrosines were also responsible for antiviral and antiproliferative activities of IFN-lambda 1. By contrast, STAT4 phosphorylation (and to some extent STAT3 activation) was independent from IL-28R/LICR2 tyrosine residues. Taken together, these observations extend the functional similarities between IFN-lambdas and type I IFNs and shed some new light on the mechanisms of activation of STAT2 and STAT4 by these cytokines.
Dumoutier
Laure
L
Ludwig Institute for Cancer Research, Brussels Branch and the Experimental Medicine Unit, Université de Louvain, B-1200 Brussels, Belgium.
Tounsi
Amel
A
Michiels
Thomas
T
Sommereyns
Caroline
C
Kotenko
Sergei V
SV
Renauld
Jean-Christophe
JC
D000998:Antiviral Agents / Q000494:pharmacology; D015153:Blotting, Western; D002455:Cell Division; D002460:Cell Line; D045744:Cell Line, Tumor; D016207:Cytokines / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism*; D007372:Interferons; D007378:Interleukins / Q000378:metabolism*; D008156:Luciferases / Q000378:metabolism; D016399:Lymphoma, T-Cell / Q000378:metabolism; D008894:Milk Proteins; D010766:Phosphorylation; D018121:Receptors, Cytokine / Q000737:chemistry* / Q000378:metabolism; D050794:STAT1 Transcription Factor; D050795:STAT2 Transcription Factor; D050796:STAT3 Transcription Factor; D050797:STAT4 Transcription Factor; D050799:STAT5 Transcription Factor; D015398:Signal Transduction; D015534:Trans-Activators / Q000378:metabolism; D014162:Transfection; D014443:Tyrosine / Q000737:chemistry*; D015854:Up-Regulation; D000095022:Interferon Lambda
D000998:Antiviral Agents; D016207:Cytokines; D004268:DNA-Binding Proteins; D007371:Interferon-gamma; D007372:Interferons; D007378:Interleukins; D008156:Luciferases; D008894:Milk Proteins; D018121:Receptors, Cytokine; D050794:STAT1 Transcription Factor; D050795:STAT2 Transcription Factor; D050796:STAT3 Transcription Factor; D050797:STAT4 Transcription Factor; D050799:STAT5 Transcription Factor; D015534:Trans-Activators; D014443:Tyrosine; C000624353:interferon-lambda, human; D000095022:Interferon Lambda; C494079:STAT1 protein, human; C494084:STAT2 protein, human; C494086:STAT3 protein, human; C494090:STAT4 protein, human; C471046:interleukin 28alpha receptor