CAS Key Laboratory of Special Pathogens and Biosafety, Wuhan Institute of Virologygrid.439104.b, Center for Biosafety Mega-Science, CAS Center for Influenza Research and Early Warning, Chinese Academy of Sciences, Wuhan, China.
University of Chinese Academy of Sciences, Beijing, China.
mBio. 2022 Jun 28;13(3):e0061522. doi: 10.1128/mbio.00615-22. Epub 2022 May 31.
Upon influenza A virus (IAV) infection, the IAV progeny ribonucleoprotein complex, with a defective viral genome, is sensed by DNA-dependent activator of interferon-regulatory factor (DAI). DAI initiates the recruitment of an array of proteins to form a multiprotein platform (PANoptosome), which triggers apoptosis, necroptosis, and pyroptosis during IAV infection. However, the mechanisms mediating the assembly of the PANoptosome are unclear. Here, we identified a scaffold protein, sperm-associated antigen 9 (SPAG9), which could interact with DAI to promote cell death during IAV infection. We further demonstrated that the cell death enhanced by SPAG9 was achieved through the DAI/SPAG9/c-Jun N-terminal kinase (JNK) axis, which could promote IAV-induced DAI-mediated cell death, including apoptosis, necroptosis, and pyroptosis. Our data further showed that the DAI/SPAG9/JNK signaling pathway enhanced the interactions among receptor-interacting serine/threonine kinase 1 (RIPK1), RIPK3, and DAI, thereby promoting IAV-induced PANoptosome formation. Overall, our study for the first time revealed a feed-forward circuit signaling pathway that enhanced IAV-induced DAI-mediated cell death, provided insights into the molecular mechanisms of cell death, and established therapeutic targets to address infectious and inflammatory diseases. Upon influenza A virus (IAV) infection, DAI is activated, recruits downstream proteins to assemble a multiprotein platform (PANoptosome), and then triggers cell death. Until now, the protein composition and assembly mechanism of the PANoptosome during IAV infection had not been elucidated. Using proximity labeling and mass spectrometry technology, we identified SPAG9 as a novel component of the PANoptosome and confirmed that SPAG9 promotes IAV-induced cell death by enhancing the interaction among RIPK1, RIPK3, and DAI. Our study will broaden the knowledge of the molecular mechanisms of cell death.
甲型流感病毒（IAV）感染后，具有缺陷病毒基因组的 IAV 子代核糖核蛋白复合物被 DNA 依赖性干扰素调节因子激活物（DAI）识别。DAI 启动一系列蛋白的募集，形成多蛋白平台（PANoptosome），在 IAV 感染过程中触发细胞凋亡、坏死性凋亡和细胞焦亡。然而，介导 PANoptosome 组装的机制尚不清楚。在这里，我们鉴定了一种支架蛋白精子相关抗原 9（SPAG9），它可以与 DAI 相互作用，促进 IAV 感染期间的细胞死亡。我们进一步证明，SPAG9 增强的细胞死亡是通过 DAI/SPAG9/c-Jun N 端激酶（JNK）轴实现的，该轴可以促进 IAV 诱导的 DAI 介导的细胞死亡，包括凋亡、坏死性凋亡和细胞焦亡。我们的数据进一步表明，DAI/SPAG9/JNK 信号通路增强了受体相互作用丝氨酸/苏氨酸激酶 1（RIPK1）、RIPK3 和 DAI 之间的相互作用，从而促进 IAV 诱导的 PANoptosome 形成。总的来说，我们的研究首次揭示了一种增强 IAV 诱导的 DAI 介导的细胞死亡的正反馈回路信号通路，为细胞死亡的分子机制提供了新的见解，并确定了治疗感染和炎症性疾病的靶点。
甲型流感病毒（IAV）感染后，DAI 被激活，募集下游蛋白组装成多蛋白平台（PANoptosome），然后引发细胞死亡。到目前为止，IAV 感染过程中 PANoptosome 的蛋白质组成和组装机制尚未阐明。使用邻近标记和质谱技术，我们鉴定出 SPAG9 是 PANoptosome 的一种新成分，并证实 SPAG9 通过增强 RIPK1、RIPK3 和 DAI 之间的相互作用来促进 IAV 诱导的细胞死亡。我们的研究将拓宽细胞死亡分子机制的知识。
