Recent Progress on the Molecular Mechanism of Quality Controls Induced by Ribosome Stalling

Abstract

Accurate gene expression is a prerequisite for all cellular processes. Cells actively promote correct protein folding, which prevents the accumulation of abnormal and non-functional proteins. Translation elongation is the fundamental step in gene expression to ensure cellular functions, and abnormal translation arrest is recognized and removed by the quality controls. Recent studies demonstrated that ribosome plays crucial roles as a hub for gene regulation and quality controls. Ribosome-interacting factors are critical for the quality control mechanisms responding to abnormal translation arrest by targeting its products for degradation. Aberrant mRNAs are produced by errors in mRNA maturation steps and cause aberrant translation and are eliminated by the quality control system. In this review, we focus on recent progress on two quality controls, Ribosome-associated Quality Control (RQC) and No-Go Decay (NGD), for abnormal translational elongation. These quality controls recognize aberrant ribosome stalling and induce rapid degradation of aberrant polypeptides and mRNAs thereby maintaining protein homeostasis and preventing the protein aggregation.

Keywords: no-go mRNA decay; ribosome; ribosome stalling; ribosome ubiquitination; ribosome-associated quality control.

FIGURE 1

Amodel for ribosome-associated protein quality control (RQC). Hel2/ZNF598 binds to the stalled ribosome and mediates ubiquitination of uS10 protein of 40S ribosomal subunit. Subsequently, RQT complex, which is composed of Slh1/Rqc2, Cue3/Rqt3, and Rqt4, binds to the ubiquitylated ribosome to trigger splitting of ribosome and RQC. Stalled polypeptide on 60S ribosome is ubiquitylated by E3 ligase Ltn1 in concerted action with Rqc1. Rqc2 mediates elongation of stalled polypeptides by the C-terminal addition of multiple alanyl and threonyl residues (CAT-tailing). A ubiquitylated polypeptide is released by Vms1 and extracted by Cdc48 for proteasomal degradation.

FIGURE 2

No-Go mRNA decay triggered by ribosome stalling. A collision of stalled ribosomes leads to ubiquitination of 40S ribosomal subunit and endonucleolytic cleavage of mRNA. The stalled ribosome at the 3′-end of 5′-NGD intermediate is split by Dom34: Hbs1 complex and the 5′-NGD intermediate is degraded by Ski complex and exosome. The stalled ribosome on the 3′-NGD intermediate may be dissociated or engaged in a restart of translation, and the 3′-NGD intermediate is degraded by Xrn1.

FIGURE 3

A unique structural interface to induce Hel2-driven quality control pathways. Model for quality control pathways induced by R(CGN)₁₂-mediated translation arrest (Ikeuchi et al., 2019). Hel2-mediated ribosome ubiquitination is required both for canonical NGD (NGD^RQC+) and RQC coupled to the disome, and that RQC-uncoupled NGD outside the disome (NGD^RQC-) takes place in a Not4-mediated monoubiquitination dependent manner. The arrowheads indicate the endonucleolytic cleavages sites in NGD. The red line indicates the rare codon cluster. Left: the RQC pathway is intact, the leading ribosome that is stalled by the arrest sequence undergoes RQC. The uS10 ubiquitination and Slh1/Rqt2-dependent subunit dissociation induce the endonucleolytic cleavages in the disome. Right: In the absence of uS10 ubiquitination and Rqt2, RQC in the first ribosome, as well as NGD in the disome, are eliminated. RQC-uncoupled NGD^RQC- takes place upstream of the disome. The figure concept has been reproduced from the original article (Ikeuchi et al., 2019).