Mechanism by which Sendai virus inhibits interferon signaling

感染仙台病毒(SeV)使细胞对干扰素(干扰素)无反应。对干扰素的拮抗作用是由于C蛋白的作用，C蛋白是由SeV P基因编码的病毒辅助蛋白。我们的研究揭示了SeV抑制干扰素信号转导的分子基础：1.在法盐条件下，SEV C蛋白与干扰素信号转导和转录激活因子(STAT)1结合，形成C-STAT1高分子复合体。2.C蛋白的C-末端半结构域与STAT1的N-末端结构域相互作用。3.C蛋白影响干扰素诱导的STAT1、STAT2和STAT3信号转导通路的磷酸化。4.C蛋白损伤STAT1去磷酸化事件。5.干扰素-α与细胞表面的I型干扰素受体结合可引起STAT1和STAT2的酪氨酸磷酸化。干扰素-α诱导的STAT2酪氨酸磷酸化可被C蛋白完全抑制。这种完全的抑制对于阻断干扰素-α信号是必不可少的。6.C蛋白抑制干扰素-γ应答的机制不同于抗-干扰素-α的机制。C蛋白使STAT1在Tyr^&lt；701&gt；和Ser^&lt；727&gt；被磷酸化。C蛋白的C末端半片段具有与全长C蛋白相当的抗干扰素-γ的能力，在体外可以阻止伽马激活因子与伽马激活序列(GAS)结合。这表明C蛋白可能通过与STAT1的相互作用而抑制GAF-GAS结合。7.我们发现不具有STAT1结合特性的C变异体可以抑制干扰素-γ反应，但不能抑制干扰素-α反应。这一独立于STAT1结合的新机制仍有待解决。

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.