51爆料

Enhanced expression of the cold鈥恠hock protein RNA binding motif 3 (RBM3) is highly neuroprotective both in vitro and in vivo. Whilst upstream signalling pathways leading to RBM3 expression have been described, the precise molecular mechanism of RBM3 cold induction remains elusive.

To identify temperature鈥恉ependent modulators of RBM3, the authors performed a genome鈥恮ide CRISPR鈥怌as9 knockout screen using RBM3鈥恟eporter human iPSC鈥恉erived neurons. They found that RBM3 mRNA and protein levels are robustly regulated by several splicing factors, with heterogeneous nuclear ribonucleoprotein H1 (HNRNPH1) being the strongest positive regulator. Splicing analysis revealed that moderate hypothermia significantly represses the inclusion of a poison exon, which, when retained, targets the mRNA for nonsense鈥恗ediated decay.

Importantly, they show that HNRNPH1 mediates this cold鈥恉ependent exon skipping via its thermosensitive interaction with a G鈥恟ich motif within the poison exon. Our study provides novel mechanistic insights into the regulation of RBM3 and provides further targets for neuroprotective therapeutic strategies.