Alternative polyadenylation releases <scp>PCBP1</scp> ‐mediated suppression of <scp>CFIm25</scp> during macrophage differentiation

CFIm25, a key component of the cleavage factor Im (CFIm) complex needed for mRNA 3' end processing, shows increased protein expression during monocyte-to-macrophage differentiation despite stable mRNA levels. We demonstrate that poly(C)-binding protein 1 (PCBP1) suppresses CFIm25 translation in monocytes by binding to its long 3' untranslated region (UTR). During differentiation, alternative polyadenylation generates a shorter CFIm25 3'UTR lacking PCBP1 binding sites. RNA immunoprecipitation confirms PCBP1 binding to the long 3'UTR, while ribosome association analysis shows enhanced ribosome recruitment upon PCBP1 depletion. PCBP1 knockdown increases CFIm25 protein in undifferentiated cells and induces macrophage differentiation markers without stimulation. These findings reveal how alternative polyadenylation controls CFIm25 expression during immune cell differentiation by modulating RNA-binding protein interactions and provide insight into post-transcriptional regulation of RNA processing factors. Impact statement This work reveals how a key regulator of mRNA processing is itself controlled through a previously uncharacterized mechanism during immune cell differentiation. Our findings provide insights into the molecular circuits governing macrophage development and identify potential therapeutic targets for inflammatory disorders where myeloid cell differentiation is dysregulated.