近日，美国加利福尼亚州南旧金山基因泰克公司Vishva M. Dixit研究团队研究出从干扰素调节因子2到干扰素调节因子1的转录控制转换驱动先天免疫细胞激活。相关论文于2026年9月22日发表在《细胞》杂志上。
干扰素调节因子2（IRF2）是一种转录因子，在小鼠和人类中防止皮肤炎症，但矛盾的是，它通过上调gasdermin D促进细胞焦亡。IRF2如何激活一些促炎基因却抑制炎症尚不清楚。研究人员表明，Irf2缺陷小鼠的皮肤炎症是由IRF1激活干扰素刺激基因（ISGs）驱动的。染色质分析揭示，IRF1和IRF2占据相同的ISG调控位点，但作为较弱的转录激活因子，IRF2限制IRF1对ISG的转录。Toll样受体（TLR）信号通过诱导Irf1有利于IRF1驱动的转录。此外，IRF1将泛素连接酶SPOP招募到ISG位点，导致IRF2的蛋白酶体降解。这种从IRF2到IRF1占据的转变增强了ISG转录。总之，这些发现定义了一个层级转录回路，其中IRF2在稳态条件下限制IRF1活性，但在免疫反应期间被置换，从而允许对先天免疫和自身炎症至关重要的IRF1依赖性基因程序。
附：英文原文
Title: Switching of transcriptional control from interferon regulatory factor 2 to interferon regulatory factor 1 drives innate immune cell activation
Author: Cristhian Cadena, Rohit Reja, Emma Bolech, Joshua D. Webster, Vasumathi Kameswaran, Marco de Simone, Cynthia Chen, Jian Jiang, Kathy Hotzel, Christopher Bjornson, Kamela Alegre, Zhenyu Tan, Heidi J. Elsaesser, Raymond Newland, Ryan Kelly, Spyros Darmanis, Bence Daniel, David G. Brooks, Ishan Deshpande, Kim Newton, Nobuhiko Kayagaki, Vishva M. Dixit
Issue&Volume: 2026-09-22
Abstract: Interferon regulatory factor 2 (IRF2) is a transcription factor that prevents skin inflammation in mice and humans but, paradoxically, promotes pyroptosis by upregulating gasdermin D. How IRF2 activates some proinflammatory genes but suppresses inflammation is unclear. We show that skin inflammation in Irf2-deficient mice is driven by IRF1 activation of interferon-stimulated genes (ISGs). Chromatin profiling reveals that IRF1 and IRF2 occupy the same ISG regulatory sites, but as a weaker transcriptional activator, IRF2 limits ISG transcription by IRF1. Toll-like receptor (TLR) signaling favors IRF1-driven transcription by inducing Irf1. In addition, IRF1 recruits the ubiquitin ligase SPOP to ISG sites, resulting in proteasomal degradation of IRF2. This shift from IRF2 to IRF1 occupancy enhances ISG transcription. Collectively, these findings define a hierarchical transcriptional circuit in which IRF2 limits IRF1 activity under homeostatic conditions but is displaced during an immune response, allowing IRF1-dependent gene programs central to innate immunity and autoinflammation.
DOI: 10.1016/j.cell.2026.08.049
Source: https://www.cell.com/cell/abstract/S0092-8674(26)01022-6