Suppressor of Cytokine Signaling (SOCS) 1 Inhibits Type I Interferon (IFN) Signaling via the Interferon α Receptor (IFNAR1)-associated Tyrosine Kinase Tyk2
Suppressor of Cytokine Signaling (SOCS) 1 Inhibits Type I Interferon (IFN) Signaling via the Interferon α Receptor (IFNAR1)-associated Tyrosine Kinase Tyk2
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DOI：
10.1074/jbc.m111.270207
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发表时间：
2011-09-30
影响因子：
4.8
通讯作者：
Hertzog, Paul J.
中科院分区：
文献类型：
--
作者：
Piganis, Rebecca A. R.;De Weerd, Nicole A.;Hertzog, Paul J.
I型IFN是宿主先天性和适应性免疫的关键参与者。IFN信号传导受到严格控制，以确保适当的免疫反应，因为失衡可能导致不受控制的炎症或对感染的反应不足。因此，重要的是要了解如何I型IFN信号调节。在这里，我们研究了细胞因子信号转导抑制因子1（SOCS 1）抑制I型IFN信号转导的机制。我们已经发现SOCS 1抑制I型IFN信号传导不是通过与IFN α受体1（IFNAR 1）受体组分的直接相互作用，而是通过与IFNAR 1相关激酶Tyk 2的相互作用。我们已经表征了参与SOCS 1和Tyk 2之间相互作用的残基/区域，并发现SOCS 1通过其SH 2结构域与Tyk 2的保守磷酸酪氨酸1054和1055相关联。SOCS 1的激酶抑制区也是其与Tyk 2相互作用和抑制IFN信号传导所必需的。我们还发现Tyk 2优先被Lys-63多聚泛素化，并且这种活化反应被SOCS 1抑制。SOCS 1抑制Tyk 2的结果不仅由于抑制Tyk 2激酶介导的STAT信号传导而导致IFN应答降低，而且还负面影响IFNAR 1表面表达，其由Tyk 2稳定。
Type I IFNs are critical players in host innate and adaptive immunity. IFN signaling is tightly controlled to ensure appropriate immune responses as imbalance could result in uncontrolled inflammation or inadequate responses to infection. It is therefore important to understand how type I IFN signaling is regulated. Here we have investigated the mechanism by which suppressor of cytokine signaling 1 (SOCS1) inhibits type I IFN signaling. We have found that SOCS1 inhibits type I IFN signaling not via a direct interaction with the IFN alpha receptor 1 (IFNAR1) receptor component but through an interaction with the IFNAR1-associated kinase Tyk2. We have characterized the residues/regions involved in the interaction between SOCS1 and Tyk2 and found that SOCS1 associates via its SH2 domain with conserved phosphotyrosines 1054 and 1055 of Tyk2. The kinase inhibitory region of SOCS1 is also essential for its interaction with Tyk2 and inhibition of IFN signaling. We also found that Tyk2 is preferentially Lys-63 polyubiquitinated and that this activation reaction is inhibited by SOCS1. The consequent effect of SOCS1 inhibition of Tyk2 not only results in a reduced IFN response because of inhibition of Tyk2 kinase-mediated STAT signaling but also negatively impacts IFNAR1 surface expression, which is stabilized by Tyk2.