Differential Regulation of Human Interferon A Gene Expression by Interferon Regulatory Factors 3 and 7
Differential Regulation of Human Interferon A Gene Expression by Interferon Regulatory Factors 3 and 7
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DOI：
10.1128/mcb.01805-08
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发表时间：
2009-06-15
影响因子：
5.3
通讯作者：
Civas, Ahmet
中科院分区：
文献类型：
--
作者：
Genin, Pierre;Lin, Rongtuan;Civas, Ahmet
副粘病毒感染后，活性干扰素调节因子3（IRF-3）和IRF-7的相对量调节人干扰素A（IFN-A）基因簇的差异表达。IRF-3表达主要激活IFN-A1和IFN-B，而IRF-7表达诱导多个IFN-A基因。IFN-A1基因表达依赖于三个启动子近端IRF元件（B、C和D模块，位于相对于mRNA起始位点的位置-98至-45）。IRF-3结合IFN-A 1的C模块，而其它IFN-A基因启动子响应IRF-7与B和D模块的结合。在IRF-7存在下，观察到IFN-A1的最大表达，其中三个模块完全占据。其他IFN-A基因的C模块中的核苷酸取代破坏IRF-3介导的转录，而D模块中的G/A取代增强IRF 7介导的表达。IRF-3对IFN-A基因表达具有双重作用，如下：与IRF-7对IFN-A1表达的协同作用和对其它IFN-A基因启动子的抑制作用。染色质免疫沉淀实验表明，瞬时结合的IRF-3和IRF-7，伴随着CBP/p300招聘的内源性IFN-A基因启动子，与转录激活，而IRF-3和CBP/p300的双相招聘抑制IFN-A基因的表达。这种调节机制有助于IFN-A基因的差异表达，并且可能对于通过RIG-I依赖性信号在不同细胞类型中产生α干扰素至关重要，从而导致先天性抗病毒免疫应答。
Differential expression of the human interferon A (IFN-A) gene cluster is modulated following paramyxovirus infection by the relative amounts of active interferon regulatory factor 3 (IRF-3) and IRF-7. IRF-3 expression activates predominantly IFN-A1 and IFN-B, while IRF-7 expression induces multiple IFN-A genes. IFN-A1 gene expression is dependent on three promoter proximal IRF elements (B, C, and D modules, located at positions -98 to -45 relative to the mRNA start site). IRF-3 binds the C module of IFN-A1, while other IFN-A gene promoters are responsive to the binding of IRF-7 to the B and D modules. Maximal expression of IFN-A1 is observed with complete occupancy of the three modules in the presence of IRF-7. Nucleotide substitutions in the C modules of other IFN-A genes disrupt IRF-3-mediated transcription, whereas a G/A substitution in the D modules enhances IRF7-mediated expression. IRF-3 exerts dual effects on IFN-A gene expression, as follows: a synergistic effect with IRF-7 on IFN-A1 expression and an inhibitory effect on other IFN-A gene promoters. Chromatin immunoprecipitation experiments reveal that transient binding of both IRF-3 and IRF-7, accompanied by CBP/p300 recruitment to the endogenous IFN-A gene promoters, is associated with transcriptional activation, whereas a biphasic recruitment of IRF-3 and CBP/p300 represses IFN-A gene expression. This regulatory mechanism contributes to differential expression of IFN-A genes and may be critical for alpha interferon production in different cell types by RIG-I-dependent signals, leading to innate antiviral immune responses.