CSDE1通过RNA依赖和磷酸化调节的液-液相分离促进病毒免疫逃逸
CSDE1 promotes viral immune evasion through RNA-dependent and phosphorylation-modulated liquid-liquid phase separation.
摘要(中文译文)
RIG-I样受体（RLRs）通过感知病毒RNA在抗病毒天然免疫中发挥关键作用。尽管液-液相分离（LLPS）已成为精细调控免疫信号的重要机制，但其在病毒RNA初始感知中的作用仍知之甚少。在此，我们鉴定出RNA结合蛋白CSDE1是RLR信号的负调控因子，可促进病毒的免疫逃逸。CSDE1缺陷的巨噬细胞表现出增强的干扰素产生，而CSDE1敲除小鼠对病毒感染表现出更强的抵抗力。在机制上，CSDE1形成依赖RNA的生物分子凝聚体，通过隔离免疫刺激性病毒RNA并使其免受RLR识别，发挥RNA感知检查点的功能。病毒感染后，活化的TBK1激酶磷酸化CSDE1，导致凝聚体解聚并解除免疫抑制。此外，CSDE1促进SARS-CoV-2核衣壳蛋白的凝聚，协同拮抗I型干扰素应答。值得注意的是，我们鉴定出一种小分子化合物，能够破坏CSDE1凝聚并有效抑制病毒复制。总之，我们的研究揭示了RLR信号中一个由磷酸化调控的、基于相分离的检查点，并确立了CSDE1凝聚体作为抗RNA病毒的有前景的治疗靶点。
Abstract
RIG-I-like receptors (RLRs) are essential for antiviral innate immunity through sensing viral RNA. Although liquid-liquid phase separation (LLPS) has emerged as a key mechanism in fine-tuning immune signaling, its role in the initial sensing of viral RNA remains poorly understood. Here, we identify the RNA-binding protein CSDE1 as a negative regulator of RLR signaling that facilitates viral immune evasion. Macrophages deficient in CSDE1 exhibit enhanced interferon production, and CSDE1-knockout mice show increased resistance to viral infection. Mechanistically, CSDE1 forms RNA-dependent biomolecular condensates that function as an RNA-sensing checkpoint by sequestering immunostimulatory viral RNAs and shielding them from RLR recognition. Upon viral infection, activated TBK1 kinase phosphorylates CSDE1, leading to condensate disassembly and relief of immune suppression. Furthermore, CSDE1 promotes condensation of the SARS-CoV-2 nucleocapsid protein, cooperatively antagonizing type I interferon responses. Notably, we identify a small molecule that disrupts CSDE1 condensation and potently suppresses viral replication. Together, our findings reveal a phosphorylation-modulated, phase separation-based checkpoint in RLR signaling and establish CSDE1 condensates as a promising therapeutic target against RNA viruses.
如何引用
AMA
Yi Zheng, Xuejing Zhang, Jinxiu Hou, Qian Guo, Zhenzhi Qin, Huiyu Yang, et al. CSDE1 promotes viral immune evasion through RNA-dependent and phosphorylation-modulated liquid-liquid phase separation.. Nature communications. 2026; doi:10.1038/s41467-026-72409-5.
APA
Yi Zheng, Xuejing Zhang, Jinxiu Hou, Qian Guo, Zhenzhi Qin, Huiyu Yang, et al (2026). CSDE1 promotes viral immune evasion through RNA-dependent and phosphorylation-modulated liquid-liquid phase separation.. Nature communications. https://doi.org/10.1038/s41467-026-72409-5
GB/T 7714
Yi Zheng, Xuejing Zhang, Jinxiu Hou, Qian Guo, Zhenzhi Qin, Huiyu Yang, et al. CSDE1 promotes viral immune evasion through RNA-dependent and phosphorylation-modulated liquid-liquid phase separation.[J]. Nature communications, 2026 doi:10.1038/s41467-026-72409-5.
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