Pasquesi Giulia Irene Maria, Allen Holly, Ivancevic Atma, Barbachano-Guerrero Arturo, Joyner Olivia, Guo Kejun, Simpson David M, Gapin Keala, Horton Isabella, Nguyen Lily L, Yang Qing, Warren Cody J, Florea Liliana D, Bitler Benjamin G, Santiago Mario L, Sawyer Sara L, Chuong Edward B
BioFrontiers Institute and Department of Molecular, Cellular & Developmental Biology, University of Colorado Boulder, Boulder, CO 80309, USA; Crnic Institute Boulder Branch, BioFrontiers Institute, University of Colorado Boulder, Boulder, CO 80303, USA.
BioFrontiers Institute and Department of Molecular, Cellular & Developmental Biology, University of Colorado Boulder, Boulder, CO 80309, USA.
Cell. 2024 Dec 26;187(26):7621-7636.e19. doi: 10.1016/j.cell.2024.11.016. Epub 2024 Dec 12.
Innate immune signaling is essential for clearing pathogens and damaged cells and must be tightly regulated to avoid excessive inflammation or autoimmunity. Here, we found that the alternative splicing of exons derived from transposable elements is a key mechanism controlling immune signaling in human cells. By analyzing long-read transcriptome datasets, we identified numerous transposon exonization events predicted to generate functional protein variants of immune genes, including the type I interferon receptor IFNAR2. We demonstrated that the transposon-derived isoform of IFNAR2 is more highly expressed than the canonical isoform in almost all tissues and functions as a decoy receptor that potently inhibits interferon signaling, including in cells infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Our findings uncover a primate-specific axis controlling interferon signaling and show how a transposon exonization event can be co-opted for immune regulation.
固有免疫信号传导对于清除病原体和受损细胞至关重要，必须严格调控以避免过度炎症或自身免疫。在此，我们发现源自转座元件的外显子可变剪接是控制人类细胞免疫信号传导的关键机制。通过分析长读长转录组数据集，我们鉴定出许多转座子外显子化事件，预计这些事件会产生免疫基因的功能性蛋白质变体，包括I型干扰素受体IFNAR2。我们证明，在几乎所有组织中，转座子衍生的IFNAR2异构体比经典异构体表达更高，并作为诱饵受体发挥作用，有效抑制干扰素信号传导，包括在感染严重急性呼吸综合征冠状病毒2（SARS-CoV-2）的细胞中。我们的研究结果揭示了一个灵长类动物特有的控制干扰素信号传导的轴，并展示了转座子外显子化事件如何被用于免疫调节。
