Subcellular mRNA Localization Regulates Ribosome Biogenesis in Migrating Cells.

Maria Dermit,Faraz K Mardakheh,Muhammad S Azman,Martin Dodel,Sarah P Blagden,J Louise Jones,Jernej Ule,Hagen Schwenzer,Flora C.Y Lee

doi:10.1016/j.devcel.2020.10.006

Abstract

SummaryTranslation of ribosomal protein-coding mRNAs (RP-mRNAs) constitutes a key step in ribosome biogenesis, but the mechanisms that modulate RP-mRNA translation in coordination with other cellular processes are poorly defined. Here, we show that subcellular localization of RP-mRNAs acts as a key regulator of their translation during cell migration. As cells migrate into their surroundings, RP-mRNAs localize to the actin-rich cell protrusions. 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 RP-mRNAs, enhancing RP synthesis, ribosome biogenesis, and the overall protein synthesis in migratory cells. In human breast carcinomas, epithelial-to-mesenchymal transition (EMT) upregulates LARP6 expression to enhance protein synthesis and support invasive growth. 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.

Highlights

Ribosome biogenesis, the highly conserved process of synthesis, processing, and assembly of ribosomal RNA and protein (RP) components into mature ribosomes (Bohnsack and Bohnsack, 2019), underpins all protein synthesis in living organisms
La-related protein 6 (LARP6)-Dependent RP-mRNA Localization Enhances RP Synthesis and Ribosome Biogenesis we investigated the functional consequence of RP-mRNA targeting to the protrusive fronts by LARP6
LARP6 Is Important for Ribosome Biogenesis, Invasion, and Proliferation of Migrating Cells Since our findings above provide a link between cell migration and regulation of ribosome biogenesis, we investigated whether LARP6 contributes toward a significant proportion of RP synthesis in migratory mesenchymal-like cells

Summary

Introduction

The highly conserved process of synthesis, processing, and assembly of ribosomal RNA (rRNA) and protein (RP) components into mature ribosomes (Bohnsack and Bohnsack, 2019), underpins all protein synthesis in living organisms. In parallel with RNA-polymerase-I-dependent regulation of rRNA transcription, translation of RP-coding mRNAs (RPmRNAs) acts as a key step in control of ribosome biogenesis in higher eukaryotes (Gentilella et al, 2015). A recent model proposes that mTORC1 phosphorylation acts as a molecular switch, converting LARP1 from a translational inhibitor to activator, leading to upregulation of RP-mRNAs translation and subsequent ribosome biogenesis (Hong et al, 2017). It is unclear whether other cellular processes can regulate RP-mRNA translation, independently of the mTORC1-LARP1 pathway, in response to further intrinsic or extrinsic inputs

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