RNA serves as direct thermo and potassium sensors via spliceswitch formed by G-quadruplex in mammals

Mammals maintain their core body temperature in a narrow range, yet how cells sense and respond to small temperature changes at the molecular level remains incompletely understood. Here, we uncover RNA G-quadruplex (rG4) motifs are significantly enriched around splice sites (SSs) of cassette exons repressed at lower temperature. Stabilizing these thermosensing RNA structures masks SSs, reducing exon inclusion. Focusing on cold-induced neuroprotective RBM3, we demonstrate rG4s near SSs of a poison exon become more stable at low temperatures, leading to exon exclusion, thereby elevating RBM3 expression by escaping nonsense-mediated decay. Additionally, increased intracellular potassium with potassium channel blocker also stabilizes rG4s and protects neuronal damage in a subarachnoid hemorrhage mouse model. Our findings unveil a mechanism how mammalian RNAs directly sense temperature and potassium perturbations, integrating them into gene expression programs via spliceswitches. This opens new avenues for treating diseases arising from splicing defect and disorders benefiting from increased RBM3 expression.