Stabilizing a mammalian RNA thermometer confers neuroprotection in subarachnoid hemorrhage

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.

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Publication Details

Journal
Nature Communications
Published
2025-09-18
DOI
https://doi.org/10.1038/s41467-025-63911-3
Citations
3
Primary Topic
Anesthesia and Neurotoxicity Research
Type
article
Field-Weighted Citation Impact
3.96
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article

Stabilizing a mammalian RNA thermometer confers neuroprotection in subarachnoid hemorrhage

Quanwei He, Ann‐Kathrin Emmerichs, Mario Schubert, Mingchang Li et al.
3 citations
Nature Communications
Anesthesia and Neurotoxicity Research
3.96
article

Stabilizing a mammalian RNA thermometer confers neuroprotection in subarachnoid hemorrhage

Quanwei He, Ann‐Kathrin Emmerichs, Mario Schubert, Mingchang Li, Xianan Qin, Florian Heyd, Liduan Zheng, Chengli Liu, Qiubai Li, Tom Haltenhof, Marco Preußner, Tianzi Wei, Stefan Meinke, Megha Ayachit, Bin Zhang, Min Zhang, Xin D. Gao, Weiming Li, Shu Chen, Yafei Huang, Deyi Liu, Li Yu, Cheng Aifang, Qin Huang, Lin Wang, Ruoxi Gao
article en
3 citations

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.

Nature CommunicationsVol. 16(1)
Union Hospital (HK), Zhejiang Sci-Tech University (CN), University of Macau (MO), Southern University of Science and Technology (CN), Wuhan University (CN), Hubei University of Science and Technology (CN), Zhejiang Provincial People's Hospital (CN), Renmin Hospital of Wuhan University (CN), Shenzhen University Health Science Center (CN), Hangzhou Medical College (CN), Huazhong University of Science and Technology (CN), King Abdullah University of Science and Technology (SA), Freie Universität Berlin (DE), Chongqing Medical University (CN)
Openalex Percentile: Top 6%
Anesthesia and Neurotoxicity Research
3.96
DOIOpen Access PDFOpenAlex
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