Subcellular mRNA localization regulates ribosome biogenesis in migrating cells

Translation of Ribosomal Protein coding mRNAs (RP-mRNAs) constitutes a key step in regulation of ribosome biogenesis, but the mechanisms which modulate RP-mRNAs translation under various cellular and environmental conditions are poorly understood. Here we show that the subcellular localization of RP-mRNAs acts as a key regulator of their translation in migrating cells. As cells migrate into their surroundings, RP-mRNAs localize to the actin-rich protrusions at the front the cells. This localization is mediated by La related protein-6 (LARP6), an RNA Binding Protein that is enriched in protrusions. Protrusions act as hotspots of translation for localized RP-mRNAs, resulting in enhancement of RP synthesis, up-regulation of ribosome biogenesis, and increased overall protein synthesis of migrating cells in a LARP6 dependent manner. In human breast carcinomas, Epithelial to Mesenchymal Transition (EMT) upregulates LARP6 expression to enhance protein synthesis, and can be targeted using a small molecule inhibitor that interferes with LARP6 RNA binding. Our findings reveal LARP6 mediated mRNA localization as a key regulator of ribosome biogenesis during cell-migration, and demonstrate a role for this process in cancer progression downstream of EMT.