Stabilizing a mammalian RNA thermometer confers neuroprotection in subarachnoid hemorrhage

Min Zhang (), Bin Zhang, Chengli Liu, Marco Preußner, Megha Ayachit, Weiming Li, Yafei Huang, Deyi Liu, Quanwei He, Ann-Kathrin Emmerichs, Stefan Meinke, Shu Chen, Lin Wang, Liduan Zheng, Qiubai Li, Qin Huang, Tom Haltenhof, Ruoxi Gao, Xianan Qin, Aifang Cheng, Tianzi Wei, Li Yu, Mario Schubert, Xin Gao, Mingchang Li () and Florian Heyd ()
Additional contact information
Min Zhang: Freie Universität Berlin
Bin Zhang: King Abdullah University of Science and Technology (KAUST)
Chengli Liu: Renmin Hospital of Wuhan University
Marco Preußner: Freie Universität Berlin
Megha Ayachit: Freie Universität Berlin
Weiming Li: Huazhong University of Science and Technology
Yafei Huang: Huazhong University of Science and Technology
Deyi Liu: Chongqing Medical University
Quanwei He: Huazhong University of Science and Technology
Ann-Kathrin Emmerichs: Freie Universität Berlin
Stefan Meinke: Freie Universität Berlin
Shu Chen: Huazhong University of Science and Technology
Lin Wang: Huazhong University of Science and Technology
Liduan Zheng: Huazhong University of Science and Technology
Qiubai Li: Huazhong University of Science and Technology
Qin Huang: Huazhong University of Science and Technology
Tom Haltenhof: Freie Universität Berlin
Ruoxi Gao: Hangzhou Medical College
Xianan Qin: Zhejiang Sci-Tech University
Aifang Cheng: University of Macau
Tianzi Wei: Southern University of Science and Technology
Li Yu: Shenzhen University
Mario Schubert: Freie Universität Berlin
Xin Gao: King Abdullah University of Science and Technology (KAUST)
Mingchang Li: Renmin Hospital of Wuhan University
Florian Heyd: Freie Universität Berlin

Nature Communications, 2025, vol. 16, issue 1, 1-19

Abstract: Abstract 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.

Date: 2025
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DOI: 10.1038/s41467-025-63911-3

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