Iron-sensitive RNA regulation by poly C-binding proteins

Iron is essential for normal cellular function. Homeostatic responses to low iron availability have long been known to rely on posttranscriptional mechanisms. Poly C-binding proteins (PCBPs) are essential RNA-binding proteins that regulate alternative splicing (AS), translation, and RNA stability. They also serve as critical iron chaperones that manage intracellular iron flux. However, the impact of cellular iron levels on the PCBP-directed transcriptome has not been globally evaluated. We found broad transcriptome changes, including AS, in response to low iron availability consistent with numerous operant posttranscriptional mechanisms that sense iron. By comparing AS directed by PCBP1 and PCBP2 to the iron-sensitive transcriptome, we found genes with iron-sensitive PCBP-mediated splicing regulation. We also found that iron chelation-induced splicing changes were attenuated with knockdown of PCBPs. Further, we demonstrate that iron chelation or mutation of PCBP1 iron binding residues enhances PCBP1 RNA association. This work highlights widespread iron-sensitive RNA regulation and identifies PCBP1 and PCBP2 as critical splicing factors contributing to this response.