Role of the interleukin (IL)-28 receptor tyrosine residues for antiviral and antiproliferative activity of IL-29/interferon-λ1 -: Similarities with type I interferon signaling
Role of the interleukin (IL)-28 receptor tyrosine residues for antiviral and antiproliferative activity of IL-29/interferon-λ1 -: Similarities with type I interferon signaling
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DOI：
10.1074/jbc.m404789200
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发表时间：
2004-07-30
影响因子：
4.8
通讯作者：
Renauld, JC
中科院分区：
文献类型：
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作者：
Dumoutier, L;Tounsi, A;Renauld, JC
干扰素-lambda1、-lambda2和-lambda3是第二类细胞因子家族的最新成员，具有抗病毒活性。它们的受体由IL-28R/可能的IL或细胞因子或受体2(IL-28R/LICR2)和IL-10Rβ两条链组成，介导STAT1、STAT2、STAT3和STAT5的酪氨酸磷酸化。在这里，我们表明，干扰素-lambda1激活该受体也可以抑制细胞增殖并诱导STAT4磷酸化，进一步扩大了与I型IFN的功能相似之处。我们使用IL-28R/LICR2突变的受体来鉴定STAT激活所需的酪氨酸，以及抗增殖和抗病毒活性。我们发现，干扰素-lambda1诱导的STAT2酪氨酸磷酸化是通过受体的343和517酪氨酸介导的，这与参与STAT2激活的I型干扰素受体的酪氨酸有一些相似之处。这两种酪氨酸也与干扰素-lambda1的抗病毒和抗增殖活性有关。相反，STAT4的磷酸化(以及在一定程度上激活STAT3)不依赖于IL-28R/LICR2酪氨酸残基。综上所述，这些观察扩大了干扰素-lambdas和I型IFN之间的功能相似性，并为这些细胞因子激活STAT2和STAT4的机制提供了一些新的线索。
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.