Differential activation of IFN regulatory factor (IRF)-3 and IRF-5 transcription factors during viral infection
Differential activation of IFN regulatory factor (IRF)-3 and IRF-5 transcription factors during viral infection
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DOI：
10.4049/jimmunol.176.12.7462
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发表时间：
2006-06-15
影响因子：
4.4
通讯作者：
Reich, Nancy C.
中科院分区：
文献类型：
--
作者：
Cheng, Tsu-Fan;Rzostek, Sabrina B.;Reich, Nancy C.
IFN调节因子（IRF）家族的成员调节对免疫应答、造血和增殖至关重要的基因表达。虽然相关的同源性在其N-末端DNA结合域，它们显示个人的功能特性。不同的性质是由调节表达、对激活信号的反应以及与DNA调节元件的相互作用的差异引起的。IRF-3广泛表达，并在病毒感染或TLR信号传导时通过丝氨酸磷酸化激活。有证据表明，激酶TANK结合激酶1和NF-κ B激酶抑制剂特异性磷酸化，从而激活IRF-3。我们评估了IRF家族的另一个成员IRF-5在病毒感染期间的贡献，因为先前的研究提供了不同的结果。磷酸化，核转位，二聚化，结合CREB结合蛋白，识别DNA，诱导基因表达的分析与IRF-3相比，作为IRF-5激活的措施。IRF-5未被病毒感染激活;然而，TANK结合激酶1或NF-κ B激酶抑制剂的表达确实提供了IRF-5的明确激活。因此，IRF-5在其活化特征方面与IRF-3不同。然而，与IRF-3激活的生物学效应相似，IRF-5的组成性活性突变促进了细胞凋亡。Bcl-x（L）的表达可抑制细胞凋亡，而Fas相关死亡结构域的显性失活突变则不能抑制细胞凋亡。这些研究支持IRF-3与IRF-5不同的激活特征，但揭示了潜在的共同生物学效应。
Members of the IFN regulatory factor (IRF) family regulate gene expression critical to immune response, hemopoiesis, and proliferation. Although related by homology at their N-terminal DNA-binding domain, they display individual functional properties. The distinct properties result from differences in regulated expression, response to activating signals, and interaction with DNA regulatory elements. IRF-3 is expressed ubiquitously and is activated by serine phosphorylation in response to viral infection or TLR signaling. Evidence indicates that the kinases TANK-binding kinase 1 and inhibitor of NF-kappa B kinase-epsilon specifically phosphorylate and thereby activate IRF-3. We evaluated the contribution of another member of the IRF family, IRF-5, during viral infection since prior studies provided varied results. Analysis of phosphorylation, nuclear translocation, dimerization, binding to CREB-binding protein, recognition of DNA, and induction of gene expression were used comparatively with IRF-3 as a measure of IRF-5 activation. IRF-5 was not activated by viral infection; however, expression of TANK-binding kinase 1 or inhibitor of NF-kappa B kinase-epsilon did provide clear activation of IRF-5. IRF-5 is therefore distinct in its activation profile from IRF-3. However, similar to the biological effects of IRF-3 activation, a constitutively active mutation of IRF-5 promoted apoptosis. The apoptosis was inhibited by expression of Bcl-x(L) but not a dominant-negative mutation of the Fas-associated death domain. These studies support the distinct activation profiles of IRF-3 in comparison to IRF-5, but reveal a potential shared biological effect.