Laboratory of Radiation Medicine, Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, West China Second University Hospital, Sichuan University, Chengdu, 610041, China.
Department of Radiation Medicine, West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu, 610041, China.
Cell Mol Immunol. 2024 Aug;21(8):856-872. doi: 10.1038/s41423-024-01185-3. Epub 2024 Jun 7.
The key role of structural cells in immune modulation has been revealed with the advent of single-cell multiomics, but the underlying mechanism remains poorly understood. Here, we revealed that the transcriptional activation of interferon regulatory factor 1 (IRF1) in response to ionizing radiation, cytotoxic chemicals and SARS-CoV-2 viral infection determines the fate of structural cells and regulates communication between structural and immune cells. Radiation-induced leakage of mtDNA initiates the nuclear translocation of IRF1, enabling it to regulate the transcription of inflammation- and cell death-related genes. Novel posttranslational modification (PTM) sites in the nuclear localization sequence (NLS) of IRF1 were identified. Functional analysis revealed that mutation of the acetylation site and the phosphorylation sites in the NLS blocked the transcriptional activation of IRF1 and reduced cell death in response to ionizing radiation. Mechanistically, reciprocal regulation between the single-stranded DNA sensors SSBP1 and IRF1, which restrains radiation-induced and STING/p300-mediated PTMs of IRF1, was revealed. In addition, genetic deletion or pharmacological inhibition of IRF1 tempered radiation-induced inflammatory cell death, and radiation mitigators also suppressed SARS-CoV-2 NSP-10-mediated activation of IRF1. Thus, we revealed a novel cytoplasm-oriented mechanism of IRF1 activation in structural cells that promotes inflammation and highlighted the potential effectiveness of IRF1 inhibitors against immune disorders.
单细胞多组学技术的出现揭示了结构细胞在免疫调节中的关键作用，但其中的潜在机制仍知之甚少。在这里，我们揭示了干扰素调节因子 1（IRF1）在应对电离辐射、细胞毒性化学物质和 SARS-CoV-2 病毒感染时的转录激活决定了结构细胞的命运，并调节结构细胞与免疫细胞之间的通讯。电离辐射诱导的 mtDNA 漏出引发 IRF1 的核转位，使其能够调节炎症和细胞死亡相关基因的转录。鉴定到了 IRF1 核定位序列（NLS）中的新翻译后修饰（PTM）位点。功能分析表明，NLS 中的乙酰化位点和磷酸化位点的突变会阻断 IRF1 的转录激活，并减少电离辐射引起的细胞死亡。在机制上，揭示了单链 DNA 传感器 SSBP1 和 IRF1 之间的相互调节关系，这种调节关系抑制了电离辐射诱导的和 STING/p300 介导的 IRF1 的 PTM。此外，IRF1 的遗传缺失或药理学抑制减轻了辐射诱导的炎症性细胞死亡，辐射缓和剂也抑制了 SARS-CoV-2 NSP-10 介导的 IRF1 激活。因此，我们揭示了一种新型的以细胞质为导向的 IRF1 在结构细胞中激活的机制，该机制促进了炎症的发生，并强调了 IRF1 抑制剂在治疗免疫紊乱方面的潜在有效性。
