Role of the interleukin (IL)-28 receptor tyrosine residues for antiviral and antiproliferative activity of IL-29/interferon-λ1. Similarities with type 1 interferon signaling

Laure Dumoutier, Amel Tounsi, Thomas Michiels, Caroline Sommereyns, Sergei V. Kotenko, Jean Christophe Renauld

Research output: Contribution to journalArticlepeer-review

276 Scopus citations

Abstract

Interferon (IFN)-λ1, -λ2, and -λ3 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-10Rβ, and mediates the tyrosine phosphorylation of STAT1, STAT2, STAT3, and STAT5. Here, we show that activation of this receptor by IFN-λ1 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-λ1-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-λ1. 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-λs and type I IFNs and shed some new light on the mechanisms of activation of STAT2 and STAT4 by these cytokines.

Original languageEnglish (US)
Pages (from-to)32269-32274
Number of pages6
JournalJournal of Biological Chemistry
Volume279
Issue number31
DOIs
StatePublished - Jul 30 2004

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Biochemistry
  • Cell Biology

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