Panthi Asmita, Ferretti Max B, Howard Olivia, Pokharel Swechha Mainali, McCracken Rhiannon, Quesnel-Vallieres Mathieu, Li Qin, Cherry Sara, Lynch Kristen W
bioRxiv. 2025 Mar 10:2025.03.10.642367. doi: 10.1101/2025.03.10.642367.
Interferon Regulatory Factor 7 (IRF7), and its homologue IRF3, are master transcriptional regulators of the innate immune response. IRF7 binds to promoters of interferon β (IFNβ) and several IFNαs as a homodimer or as a heterodimer with IRF3 to drive expression of these type I IFNs, which in turn activate downstream signaling pathways to promote expression of antiviral genes. Here we demonstrate that alternative splicing of the first intron within the coding region of IRF7 is highly regulated across immune tissues and in response to immunologic signals including viral infection. Retention of this intron generates an alternative translation start site, resulting in a N-terminally extended form of the protein (exIRF7) with distinct function from the canonical version of IRF7 (cIRF7). We find that exIRF7 uniquely activates a gene expression program, including IFNβ, in response to innate immune triggers. Mechanistically, this enhanced activity of exIRF7 relative to cIRF7 is through increased homodimerization and association with IRF3 on DNA. Furthermore, the enhanced transcriptional activity of exIRF7 controls viral infection to a greater extent than cIRF7, demonstrating that alternative splicing of IRF7 is a previously unrecognized mechanism used by cells to tune the interferon response to control viral infections and other immune challenges.
Intron retention in the human IRF7 gene generates a distinct protein isoform that differs in the N-terminus.IRF7 intron retention is regulated in a stimuli- and cell-type specific manner.The extended version of IRF7, produced by intron retention, exhibits enhanced transcriptional activation of type I interferon genes.Cells expressing the extended version of IRF7 are more resistant to viral infection.
干扰素调节因子7（IRF7）及其同源物IRF3是先天性免疫反应的主要转录调节因子。IRF7以同二聚体形式或与IRF3形成异二聚体的形式与干扰素β（IFNβ）和几种IFNα的启动子结合，以驱动这些I型干扰素的表达，而这些I型干扰素又激活下游信号通路以促进抗病毒基因的表达。在此，我们证明IRF7编码区内第一个内含子的可变剪接在免疫组织中受到高度调控，并对包括病毒感染在内的免疫信号作出反应。该内含子的保留产生了一个可变翻译起始位点，导致蛋白质的N端延伸形式（exIRF7），其功能与IRF7的经典形式（cIRF7）不同。我们发现exIRF7在对先天性免疫触发作出反应时独特地激活了一个基因表达程序，包括IFNβ。从机制上讲，exIRF7相对于cIRF7的这种增强活性是通过增加同二聚化以及与DNA上的IRF3的结合来实现的。此外，exIRF7增强的转录活性比cIRF7在更大程度上控制病毒感染，这表明IRF7的可变剪接是细胞用来调节干扰素反应以控制病毒感染和其他免疫挑战的一种先前未被认识的机制。
人类IRF7基因中的内含子保留产生了一种在N端不同的独特蛋白质异构体。IRF7内含子保留以刺激和细胞类型特异性方式受到调控。由内含子保留产生的IRF7延伸版本对I型干扰素基因表现出增强的转录激活作用。表达IRF7延伸版本的细胞对病毒感染更具抗性。
