The E3 ubiquitin ligase RNF10 modifies 40S ribosomal subunits of ribosomes compromised in translation.

Aitor Garzia,Thomas Tuschl,Cindy Meyer

doi:10.1016/j.celrep.2021.109468

Abstract

Reversible monoubiquitination of small subunit ribosomal proteins RPS2/uS5 and RPS3/uS3 has been noted to occur on ribosomes involved in ZNF598-dependent mRNA surveillance. Subsequent deubiquitination of RPS2 and RPS3 by USP10 is critical for recycling of stalled ribosomes in a process known as ribosome-associated quality control. Here, we identify and characterize the RPS2- and RPS3-specific E3 ligase Really Interesting New Gene (RING) finger protein 10 (RNF10) and its role in translation. Overexpression of RNF10 increases 40S ribosomal subunit degradation similarly to the knockout of USP10. Although a substantial fraction of RNF10-mediated RPS2 and RPS3 monoubiquitination results from ZNF598-dependent sensing of collided ribosomes, ZNF598-independent impairment of translation initiation and elongation also contributes to RPS2 and RPS3 monoubiquitination. RNF10 photoactivatable ribonucleoside-enhanced crosslinking and immunoprecipitation (PAR-CLIP) identifies crosslinked mRNAs, tRNAs, and 18S rRNAs, indicating recruitment of RNF10 to ribosomes stalled in translation. These impeded ribosomes are tagged by ubiquitin at their 40S subunit for subsequent programmed degradation unless rescued by USP10.

Highlights

Eukaryotic cells have evolved co-translational quality-control mechanisms for monitoring protein synthesis in order to eliminate aberrant mRNAs and their nascent polypeptides, as well as malfunctioning ribosomes (Brandman and Hegde, 2016)
Eukaryotic cells are equipped with surveillance mechanisms to detect and eliminate numerous types of aberrant mRNAs, such as mRNAs containing a premature stop codon typically eliminated by the nonsense-mediated mRNA decay (NMD) pathway, mRNAs containing premature poly(A)-tails typically eliminated by non-stop decay (NSD), and truncated, highly structured or rare codon-containing mRNAs eliminated by no-go decay (NGD) (Shoemaker and Green, 2012)
The E3 ligase RNF10 ubiquitinates ribosomal proteins RPS2 and RPS3 The complex composed of the RNA-binding G3BP1 family and deubiquitinase USP10 is essential for deubiquitination of RPS2, RPS3, and RPS10 and recycling of 40S ribosomal subunits exiting ribosome-associated quality control (RQC) (Meyer et al, 2020)

Summary

Introduction

Eukaryotic cells have evolved co-translational quality-control mechanisms for monitoring protein synthesis in order to eliminate aberrant mRNAs and their nascent polypeptides, as well as malfunctioning ribosomes (Brandman and Hegde, 2016). Eukaryotic cells are equipped with surveillance mechanisms to detect and eliminate numerous types of aberrant mRNAs, such as mRNAs containing a premature stop codon typically eliminated by the nonsense-mediated mRNA decay (NMD) pathway, mRNAs containing premature poly(A)-tails typically eliminated by non-stop decay (NSD), and truncated, highly structured or rare codon-containing mRNAs eliminated by no-go decay (NGD) (Shoemaker and Green, 2012). These pathways are of fundamental importance to prevent the production of erroneous protein products prone to misfolding and aggregation (Jamar et al, 2018). This leads to a process defined as ribosome-associated quality control (RQC), which is responsible for the degradation of aberrant mRNAs and nascent polypeptides (Brandman and Hegde, 2016; Joazeiro, 2019)

Results

Discussion

Conclusion