TDP-43 binds to RNA G-quadruplex structure and regulates mRNA stability and translation.

TDP-43 is a hallmark protein associated with neurodegenerative diseases. Recent studies revealed TDP-43 as an RNA G-quadruplex (rG4)-binding protein, impacting mRNA transport and function. However, our knowledge of the TDP-43-RNA secondary structure interaction and information on its specific rG4 targets are limited. Herein, we show that TDP-43 exhibits a preference for binding to the rG4 under K+ condition using high-throughput RNA bind-n-seq. Besides, we find that the loss of TDP-43 contributes to a transcriptome-wide decrease in mRNA structure using SHALiPE-seq technology. By analyzing the SHALiPE-seq data of TDP-43-binding sites, we demonstrate that the reduction in structuredness is likely due to the loss of TDP-43 binding to the RNA targets, especially in the 3'UTR. Importantly, our transcript-specific investigation reveals that TDP-43 binds to 3'UTR rG4 of SLC1A5 transcript, promoting its mRNA stability and translation. Removing the rG4 and incorporating BRACO-19 competition result in translation inhibition of SLC1A5, highlighting the importance of rG4 in gene regulation by TDP-43. Our findings not only offer new insights into the role of TDP-43 in regulating RNA structures such as rG4 but also contribute to a better understanding of its broader functions and provide potential targets for therapeutic strategies in TDP-43-related diseases.