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Mechanism by which Sendai virus inhibits interferon signaling

仙台病毒抑制干扰素信号传导的机制

基本信息

批准号：
13670294
负责人：
GOTOH Bin
金额：
$ 2.37万
依托单位：
福井医科大学
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2001
资助国家：
日本
起止时间：
2001 至 2003
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-13670294/
关键词：
Sendai virus C protein accessory proteins STAT1 STAT2 Interferon signaling phosphorylation GAF GAS パラミクソウイルス STATs 免疫回避

项目摘要

Infection with Sendai virus (SeV) renders cells unresponsive to interferon (IFN). The antagonism to IFN is due to the functions of C protein, which is viral accessory protein encoded by the SeV P gene. Our studies have revealed a molecular basis for the mechanism by which SeV inhibits IFN signaling : 1. SeV C protein binds to the signal transducer and activator of transcription (STAT) 1, a key factor on the IFN signaling pathways, resulting in formation of C-STAT1 high molecular mass complexes under the law salt conditions. 2. The C-terminal half domain of the C protein interacts with the N-terminal domain of STAT1. 3.C protein affects IFN-stimulated phosphorylation of STATs including STAT1, STAT2, and STAT3. 4. C protein impairs the STAT1 dephosphorylation event. 5. Binding of IFN-α to the type I IFN receptor on the cell surface causes tyrosine phosphorylation of STAT1 and STAT2. The IFN-α stimulated tyrosine phosphorylation of STAT2 is completely inhibited by C protein. This complete inhibition is essential for the blockade of IFN-α signaling. 6. Mechanism by which C protein inhibits the IFN-γ response is different from the anti-IFN-α mechanism. C protein allows STAT1 to be phosphorylated at both Tyr^<701> and Ser^<727>. The C-terminal half fragment of C protein, which has the anti-IFN-γ ability comparable to that of the full-size C, prevents the gamma-activated factor (GAF) from binding to a gamma-activated sequence (GAS) site in vitro. This suggests the possibility that the C protein inhibits the GAF-GAS binding through the interaction with STAT1. 7. We found that a C variant with no STAT1-binding property could inhibit the IFN-γ response but not the IFN-α response. This novel mechanism independent of the STAT1-binding remains to be solved.

仙台病毒（SeV）感染使细胞对干扰素（IFN）无反应。SeV P基因编码的病毒辅助蛋白C蛋白具有拮抗IFN的作用。我们的研究揭示了SeV抑制IFN信号传导机制的分子基础：1. SeV C蛋白与IFN信号通路上的关键因子--信号转导子和转录激活子（STAT）1结合，在低盐条件下形成C-STAT 1高分子量复合物。2. C蛋白的C端半结构域与STAT 1的N端结构域相互作用。3.C蛋白影响IFN刺激的STAT磷酸化，包括STAT 1，STAT 2和STAT 3。4. C蛋白损害STAT 1去磷酸化事件。5. IFN-α与细胞表面I型IFN受体的结合导致STAT 1和STAT 2的酪氨酸磷酸化。IFN-α刺激的STAT 2酪氨酸磷酸化被C蛋白完全抑制。这种完全抑制对于阻断IFN-α信号传导至关重要。6. C蛋白抑制IFN-γ应答的机制与抗IFN-α机制不同。C蛋白允许STAT 1在Tyr-1和Ser-1处磷酸化<701><727>。C蛋白的C端半片段具有与全长C相当的抗IFN-γ能力，其在体外阻止γ激活因子（GAF）与γ激活序列（GAS）位点结合。这表明C蛋白通过与STAT 1相互作用抑制GAF-GAS结合的可能性。7.我们发现没有STAT 1结合特性的C变体可以抑制IFN-γ反应，但不能抑制IFN-α反应。这种新的机制独立的STAT 1结合仍有待解决。