Co-Translational Quality Control Induced by Translational Arrest

Abstract

Genetic mutations, mRNA processing errors, and lack of availability of charged tRNAs sometimes slow down or completely stall translating ribosomes. Since an incomplete nascent chain derived from stalled ribosomes may function anomalously, such as by forming toxic aggregates, surveillance systems monitor every step of translation and dispose of such products to prevent their accumulation. Over the past decade, yeast models with powerful genetics and biochemical techniques have contributed to uncovering the mechanism of the co-translational quality control system, which eliminates the harmful products generated from aberrant translation. We here summarize the current knowledge of the molecular mechanism of the co-translational quality control systems in yeast, which eliminate the incomplete nascent chain, improper mRNAs, and faulty ribosomes to maintain cellular protein homeostasis.

Keywords: mRNA decay; non-canonical ribosome dissociation; protein degradation; quality control; ribosome collision; transrational arrest; ubiquitination.

Figure 1

The response to the ribosome collision. Several sensor proteins detect the ribosome collision and induce different pathways. Hel2 (Znf598 in mammals) induces ribosome-associated quality control (RQC) and the no-go decay (NGD). The general control nonderepressible (GCN) complex induces an integrated stress response (ISR). ZAKα induces cell cycle arrest or apoptosis via the p38 or c-Jun pathway, respectively, which are called ribotoxic stress response (RSR).

Figure 2

Ribosome quality control triggering step. The ribosome collision is recognized by E3 ligase Hel2, which elongates the K63-linked poly-ubiquitination on the ribosomal protein uS10. The K63-linked polyubiquitination is recognized by the RQT complex via its components Cue3 and Rqt4, inducing the non-canonical ribosome dissociation for the leading stalling ribosome to resume translation.

Figure 3

Degradation pathway of incomplete nascent chains. After the Hel2-mediated ribosome splitting, the incomplete nascent chain on the dissociated 60S subunit is recognized by Rqc2 and E3 ligase Ltn1 and is ubiquitinated. If Ltn1 cannot ubiquitinate the nascent chain, e.g., no lysine residue within the Ltn1-accessible region, Rqt2 recruits the alanine- (Ala-) or threonine- (Thr-) charged tRNAs to extend the c-terminal of the nascent chain (CATylation). It contributes to pushing out the lysine residue within the ribosome tunnel. After ubiquitination of the nascent chain, peptidyl-tRNA is cleaved by Vms1 at the cytosine-cytosine-adenine (CCA) end of tRNA; afterward, the nascent chain is extracted from the ribosome tunnel by Cdc48 and degraded by the proteasome.

Figure 4

Degradation pathway for the non-functional ribosome. The decoding-defective ribosomes are initially monoubiquitinated by Mag2 and then polyubiquitinated by Fap1 to initiate 18S nonfunctional rRNA decay (selective degradation of small subunit). In the first selection, Mag2 recognizes the slow translating ribosome and monoubiquitinates ribosomal protein uS3. After the first selection step, Fap1 recognizes stalling monoribosomes and elongates the K63-linked polyubiquitin chain on the Mag2-mediated monoubiquitinated uS3. This tandem ubiquitin system triggers the non-functional 18S rRNA decay.