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

Dumoutier, Laure;Tounsi, Amel;Michiels, Thomas;Sommereyns, Caroline;Renauld, Jean-Christophe;et.al.
(2004) Journal of Biological Chemistry — Vol. 279, n° 31, p. 32269-32274 (2004)

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Abstract
Interferon (IFN)-lambda1, -lambda2, and -lambda3 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-10Rbeta, and mediates the tyrosine phosphorylation of STAT1, STAT2, STAT3, and STAT5. Here, we show that activation of this receptor by IFN-lambda1 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-lambda1-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-lambda1. 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.
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Dumoutier, L., Tounsi, A., Michiels, T., Sommereyns, C., Kotenko, S., & Renauld, J.-C. (2004). 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. Journal of Biological Chemistry, 279(31), 32269-32274. https://doi.org/10.1074/jbc.M404789200 (Original work published 2004)