Mechanism by which Sendai virus inhibits interferon signaling

仙台病毒（SeV）感染使细胞对干扰素（IFN）无反应。对IFN的拮抗作用是由于C蛋白的功能，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和转录激活因子（STAT） 1结合，在盐盐条件下形成C- stat1高分子质量复合物。2. C蛋白的C端半结构域与STAT1的n端结构域相互作用。3.C蛋白影响ifn刺激的STAT1、STAT2和STAT3的磷酸化。4. C蛋白损害STAT1去磷酸化事件。5. IFN-α与细胞表面的I型IFN受体结合导致STAT1和STAT2的酪氨酸磷酸化。IFN-α刺激的酪氨酸磷酸化STAT2被C蛋白完全抑制。这种完全抑制对于阻断IFN-α信号通路至关重要。6. C蛋白抑制IFN-γ反应的机制与抗IFN-α的机制不同。C蛋白允许STAT1在Tyr^<701>和Ser^<727>位点磷酸化。C蛋白的C端半片段具有与全尺寸C相当的抗ifn -γ能力，可在体外阻止γ活化因子（GAF）结合到γ活化序列（GAS）位点。这表明C蛋白可能通过与STAT1的相互作用抑制GAF-GAS结合。7. 我们发现，不具有stat1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.