RT Journal Article
SR Electronic
T1 Subcellular mRNA localization regulates ribosome biogenesis in migrating cells
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 829739
DO 10.1101/829739
A1 Maria Dermit
A1 Martin Dodel
A1 Flora C. Y. Lee
A1 Muhammad S. Azman
A1 Hagen Schwenzer
A1 J. Louise Jones
A1 Sarah P. Blagden
A1 Jernej Ule
A1 Faraz K. Mardakheh
YR 2019
UL http://biorxiv.org/content/early/2019/11/04/829739.abstract
AB Summary 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.