Translation Efficiency and Degradation of ER-Associated mRNAs Modulated by ER-Anchored poly(A)-Specific Ribonuclease (PARN).

Tian-Li Duan,Guang-Jun He,Yong-Bin Yan,Han Jiao

doi:10.3390/cells9010162

Abstract

Translation is spatiotemporally regulated and endoplasmic reticulum (ER)-associated mRNAs are generally in efficient translation. It is unclear whether the ER-associated mRNAs are deadenylated or degraded on the ER surface in situ or in the cytosol. Here, we showed that ER possessed active deadenylases, particularly the poly(A)-specific ribonuclease (PARN), in common cell lines and mouse tissues. Consistently, purified recombinant PARN exhibited a strong ability to insert into the Langmuir monolayer and liposome. ER-anchored PARN was found to be able to reshape the poly(A) length profile of the ER-associated RNAs by suppressing long poly(A) tails without significantly influencing the cytosolic RNAs. The shortening of long poly(A) tails did not affect global translation efficiency, which suggests that the non-specific action of PARN towards long poly(A) tails was beyond the scope of translation regulation on the ER surface. Transcriptome sequencing analysis indicated that the ER-anchored PARN trigged the degradation of a small subset of ER-enriched transcripts. The ER-anchored PARN modulated the translation of its targets by redistributing ribosomes to heavy polysomes, which suggests that PARN might play a role in dynamic ribosome reallocation. During DNA damage response, MK2 phosphorylated PARN-Ser557 to modulate PARN translocation from the ER to cytosol. The ER-anchored PARN modulated DNA damage response and thereby cell viability by promoting the decay of ER-associated MDM2 transcripts with low ribosome occupancy. These findings revealed that highly regulated communication between mRNA degradation rate and translation efficiency is present on the ER surface in situ and PARN might contribute to this communication by modulating the dynamic ribosome reallocation between transcripts with low and high ribosome occupancies.

Highlights

Diverse pathways that serve to modulate transcript abundance and translation efficiency dynamically regulate gene expression levels
endoplasmic reticulum (ER)-associated mRNAs are believed to translate with a high efficiency and translation repression will release the ER-bound mRNAs back to the cytosol [43,44,69]
It is worth noting that, during ER stress, IRE1, an ER-localized endoribonuclease, can be activated to splice XBP1 mRNA to a translatable form [72], which implies that the ER surface might provide an interface for efficient translation, and for prerequisite translation regulation

Summary

Introduction

Diverse pathways that serve to modulate transcript abundance and translation efficiency dynamically regulate gene expression levels. The rates of transcription, maturation, transportation, and degradation mainly determined the abundance of transcripts [1]. After transported from the nucleus to cytoplasm, the abundance of mature mRNAs is negatively regulated by the decay rate. The bulk of eukaryotic mRNAs are degraded in a deadenylation-dependent pathway, in which deadenylation is the first and rate-limiting step [2,3]. The long poly(A) tails at the mRNA 30 -end are removed by deadenylases, a group of 30 -exonucleases with high specificity of poly(A) as the substrate [1,2,3,4].

Methods

Results

Conclusion