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The Structural Basis of IRF-3 Activation upon Phosphorylation
The Journal of Immunology ( IF 3.6 ) Pub Date : 2020-08-21 , DOI: 10.4049/jimmunol.2000026
Tao Jing 1 , Baoyu Zhao 1 , Pengbiao Xu 1 , Xinsheng Gao 1 , Lei Chi 1, 2 , Huajun Han 1 , Banumathi Sankaran 3 , Pingwei Li 4
Affiliation  

Key Points The crystal structures of phosphorylated IRF-3/CBP complexes have been determined. Both Ser386 and Ser396 are involved in IRF-3 activation, but Ser386 is more crucial. The mechanism of mouse IRF-3 activation is similar to but distinct from human IRF-3. The innate immune system is the first line of defense against bacterial and viral infections. The recognition of pathogen-associated molecular patterns by the RIG-I–like receptors, TLRs, and cGAS leads to the induction of IFN-I by activating the transcription factor IRF-3. Although the mechanism of IRF-3 activation has been extensively studied, the structural basis of IRF-3 activation upon phosphorylation is not fully understood. In this study, we determined the crystal structures of phosphorylated human and mouse IRF-3 bound to CREB-binding protein (CBP), which reveal that phosphorylated IRF-3 forms a dimer via pSer386 (pSer379 in mouse IRF-3) and a downstream pLxIS motif. Size-exclusion chromatography and cell-based studies show that mutations of key residues interacting with pSer386 severely impair IRF-3 activation and IFN-β induction. By contrast, phosphorylation of Ser396 within the pLxIS motif of human IRF-3 only plays a moderate role in IRF-3 activation. The mouse IRF-3/CBP complex structure reveals that the mechanism of mouse IRF-3 activation is similar but distinct from human IRF-3. These structural and functional studies reveal the detailed mechanism of IRF-3 activation upon phosphorylation.

中文翻译:

磷酸化后 IRF-3 激活的结构基础

关键点 磷酸化 IRF-3/CBP 复合物的晶体结构已经确定。Ser386 和 Ser396 都参与了 IRF-3 的激活,但 Ser386 更为关键。小鼠 IRF-3 的激活机制与人类 IRF-3 相似但不同。先天免疫系统是抵御细菌和病毒感染的第一道防线。RIG-I 样受体、TLR 和 cGAS 对病原体相关分子模式的识别导致通过激活转录因子 IRF-3 诱导 IFN-I。尽管 IRF-3 激活的机制已被广泛研究,但尚未完全了解磷酸化后 IRF-3 激活的结构基础。在这项研究中,我们确定了与 CREB ​​结合蛋白 (CBP) 结合的磷酸化人和小鼠 IRF-3 的晶体结构,这表明磷酸化的 IRF-3 通过 pSer386(小鼠 IRF-3 中的 pSer379)和下游 pLxIS 基序形成二聚体。尺寸排阻色谱和基于细胞的研究表明,与 pSer386 相互作用的关键残基的突变会严重损害 IRF-3 激活和 IFN-β 诱导。相比之下,人 IRF-3 的 pLxIS 基序中 Ser396 的磷酸化仅在 IRF-3 激活中起中等作用。小鼠IRF-3/CBP复合结构揭示小鼠IRF-3激活机制与人IRF-3相似但不同。这些结构和功能研究揭示了 IRF-3 磷酸化激活的详细机制。尺寸排阻色谱和基于细胞的研究表明,与 pSer386 相互作用的关键残基的突变会严重损害 IRF-3 激活和 IFN-β 诱导。相比之下,人 IRF-3 的 pLxIS 基序中 Ser396 的磷酸化仅在 IRF-3 激活中起中等作用。小鼠IRF-3/CBP复合结构揭示小鼠IRF-3激活机制与人IRF-3相似但不同。这些结构和功能研究揭示了 IRF-3 磷酸化激活的详细机制。尺寸排阻色谱和基于细胞的研究表明,与 pSer386 相互作用的关键残基的突变会严重损害 IRF-3 激活和 IFN-β 诱导。相比之下,人 IRF-3 的 pLxIS 基序中 Ser396 的磷酸化仅在 IRF-3 激活中起中等作用。小鼠IRF-3/CBP复合结构揭示小鼠IRF-3激活机制与人IRF-3相似但不同。这些结构和功能研究揭示了 IRF-3 磷酸化激活的详细机制。
更新日期:2020-08-21
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