Control of Translation and miRNA-Dependent Repression by a Novel Poly(A) Binding Protein, hnRNP-Q

Yuri V Svitkin,Alexey E Karetnikov,Nahum Sonenberg,Arkady Khoutorsky,Marc R Fabian,Ivan Topisirovic,Tommy Alain,Akiko Yanagiya,Sandra Perreault,Jens Lykke-Andersen

doi:10.1371/journal.pbio.1001564

Yuri V Svitkin, Alexey E Karetnikov + Show 8 more

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https://doi.org/10.1371/journal.pbio.1001564

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Abstract

Author SummaryThe regulation of mRNA translation and stability is of paramount importance for almost every cellular function. In eukaryotes, the poly(A) binding protein (PABP) is a central regulator of both global and mRNA-specific translation. PABP simultaneously interacts with the 3′ poly(A) tail of the mRNA and the eukaryotic translation initiation factor 4G (eIF4G). These interactions circularize the mRNA and stimulate translation. PABP also regulates specific mRNAs by promoting miRNA-dependent deadenylation and translational repression. A key step in understanding PABP's functions is to identify factors that affect its association with the poly(A) tail. Here we show that the cytoplasmic isoform of the mouse heterogeneous nuclear ribonucleoprotein Q (hnRNP-Q2/SYNCRIP), which exhibits binding preference to poly(A), interacts with the poly(A) tail by default when PABP binding is inhibited. In addition, hnRNP-Q2 competes with PABP for binding to the poly(A) tail. Depleting hnRNP-Q2 stimulates translation in cell-free extracts and in cultured cells, in agreement with its function as translational repressor. In addition, hnRNP-Q2 impeded miRNA-mediated deadenylation and repression of target mRNAs, which requires PABP. Thus, competition from hnRNP-Q2 provides a novel mechanism by which multiple functions of PABP are regulated. This regulation could play important roles in various biological processes, such as development, viral infection, and human disease.

Highlights

Proteins that form dynamic multiprotein complexes with eukaryotic mRNAs play important roles in the control of gene expression [1]
The stimulatory effects of the cap structure and the poly(A) tail on translation are synergistic. eukaryotic initiation factor 4E (eIF4E) is a subunit of the eIF4F complex, which includes eIF4A, an RNA-dependent ATPase/RNA helicase, and eukaryotic translation initiation factor 4G (eIF4G), a high-molecular-weight scaffolding protein [5]. eIF4G interacts with poly(A) binding protein (PABP) [6,7,8] and eIF3, which bridges between the eIF4G and 40S ribosomal subunit [9]
PABP simultaneously interacts with the 39 poly(A) tail of the mRNA and the eukaryotic translation initiation factor 4G

Summary

Introduction

Proteins that form dynamic multiprotein complexes with eukaryotic mRNAs play important roles in the control of gene expression [1]. During translation initiation, which is the rate-limiting and most regulated step of protein synthesis, the 80S ribosome is recruited to the mRNA and positioned at the initiation codon [4]. This process is facilitated by the binding of eukaryotic initiation factor 4E (eIF4E) to the m7G cap structure at the 59 end of the mRNA and poly(A) binding protein (PABP) to the 39 poly(A) tail. EIF4G interacts with PABP [6,7,8] and eIF3, which bridges between the eIF4G and 40S ribosomal subunit [9] These interactions circularize the mRNA [10] and enhance translation (reviewed in [11,12,13])

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