An Alternative Splicing Isoform of MITA Antagonizes MITA-Mediated Induction of Type I IFNs
An Alternative Splicing Isoform of MITA Antagonizes MITA-Mediated Induction of Type I IFNs
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DOI：
10.4049/jimmunol.1300798
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发表时间：
2014-02-01
影响因子：
4.4
通讯作者：
Chen, Xinwen
中科院分区：
文献类型：
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作者：
Chen, Honghe;Pei, Rongjuan;Chen, Xinwen
干扰素调节转录因子3激活介体（Mediator of IFN Regulatory Transcription Factor 3 Activation，MITA）是介导I型干扰素诱导的重要衔接蛋白。在这项研究中，我们确定了一个选择性剪接异构体的MITA缺乏外显子7，称为MITA相关蛋白（MRP）。MRP与MITA共有N端氨基酸1-253，但在羧基端具有独特的30个氨基酸序列，因此缺乏保守的结构域，包括TANK结合激酶1（TBK 1）和环二鸟苷酸结合结构域。MRP在多种组织和不同的细胞系中表达。MRP的过表达抑制了仙台病毒感染和环二鸟苷酸处理引起的MITA介导的IFN-β启动子的激活，但增强了HSV-1感染引起的激活。有趣的是，MRP表达在仙台病毒感染后降低，但在HSV-1感染后上调。MRP的过表达通过破坏MITA-TBK 1相互作用来抑制MITA介导的经由TBK 1-IFN调节转录因子3的IFN-β诱导。然而，NF-κ B通路仍然被MRP激活，因为MRP保留了与NF-κ B（i kappa B）激酶的可诱导抑制剂相互作用的能力。因此，MRP作为MITA介导的IFN产生诱导的显性负调节因子。
Mediator of IFN regulatory transcription factor 3 activation (MITA) is an important adaptor protein to mediate the induction of type I IFNs. In this study, we identified an alternatively spliced isoform of MITA lacking exon 7, termed MITA-related protein (MRP). MRP shares the N-terminal portion aa 1-253 with MITA but possesses a unique 30-aa sequence at the carboxyl terminal part, therefore lacking the conserved domains including TANK-binding kinase 1 (TBK1) and cyclic diguanylate binding domain. MRP is expressed in multiple tissues and distinct cell lines. Overexpression of MRP inhibited MITA-mediated activation of IFN-beta promoter by sendai virus infection and cyclic diguanylate treatment but enhanced that in HSV-1 infection. Interestingly, MRP expression was reduced after Sendai virus infection but was upregulated after HSV-1 infection. Overexpression of MRP inhibited MITA-mediated induction of IFN-beta via TBK1-IFN regulatory transcription factor 3 by disrupting the MITA-TBK1 interaction. However, NF-kappa B pathway was still activated by MRP, as MRP retained the ability to interact with inducible inhibitor of NF-kappa B (i kappa B) kinase. Thus, MRP acts as a dominant negative regulator of MITA-mediated induction of IFN production.