Zhang Min, Zhang Bin, Liu Chengli, Preußner Marco, Ayachit Megha, Li Weiming, Huang Yafei, Liu Deyi, He Quanwei, Emmerichs Ann-Kathrin, Meinke Stefan, Chen Shu, Wang Lin, Zheng Liduan, Li Qiubai, Huang Qin, Haltenhof Tom, Gao Ruoxi, Qin Xianan, Cheng Aifang, Wei Tianzi, Yu Li, Schubert Mario, Gao Xin, Li Mingchang, Heyd Florian
Institut für Chemie und Biochemie, RNA Biochemie, Freie Universität Berlin, Berlin, Germany.
Guangdong Key Laboratory for Biomedical Measurements and Ultrasound Imaging, National-Regional Key Technology Engineering Laboratory for Medical Ultrasound, School of Biomedical Engineering, Shenzhen University Medical School, Shenzhen University, Shenzhen, China.
Nat Commun. 2025 Sep 18;16(1):8319. doi: 10.1038/s41467-025-63911-3.
Mammals tightly regulate their core body temperature, yet how cells sense and respond to small temperature changes remains incompletely understood. Here, we discover RNA G-quadruplexes (rG4s) as key thermosensors enriched near splice sites of cold-repressed exons. These thermosensing RNA structures, when stabilized, mask splice sites, reducing exon inclusion. Specifically, rG4s near splice sites of a cold-repressed poison exon in the neuroprotective RBM3 are stabilized at low temperatures, leading to exon exclusion. This enables evasion of nonsense-mediated decay, increasing RBM3 expression at cold. Importantly, stabilizing rG4 through increasing intracellular potassium with an FDA-approved potassium channel blocker, mimics the hypothermic effect on alternative splicing, thereby increasing RBM3 expression, leading to RBM3-dependent neuroprotection in a mouse model of subarachnoid hemorrhage. Our findings unveil a mechanism how mammalian RNAs directly sense temperature and potassium perturbations, integrating them into gene expression programs. This opens new avenues for treating diseases arising from splicing defects and disorders benefiting from therapeutic hypothermia, especially hemorrhagic stroke.
哺乳动物严格调节其核心体温，但细胞如何感知并响应微小的温度变化仍未完全清楚。在此，我们发现RNA G-四链体（rG4s）是富集于冷抑制外显子剪接位点附近的关键热传感器。这些热感应RNA结构稳定时会掩盖剪接位点，减少外显子包含。具体而言，神经保护因子RBM3中一个冷抑制毒性外显子剪接位点附近的rG4s在低温下稳定，导致外显子排除。这使得无义介导的衰变得以逃避，增加了RBM3在低温时的表达。重要的是，用一种FDA批准的钾通道阻滞剂增加细胞内钾来稳定rG4，模拟了低温对可变剪接的影响，从而增加RBM3表达，在蛛网膜下腔出血小鼠模型中导致RBM3依赖性神经保护。我们的发现揭示了哺乳动物RNA如何直接感知温度和钾紊乱，并将它们整合到基因表达程序中的机制。这为治疗由剪接缺陷引起的疾病以及受益于治疗性低温的疾病，尤其是出血性中风，开辟了新途径。
