Protecting the proteome: Eukaryotic cotranslational quality control pathways

Abstract

The correct decoding of messenger RNAs (mRNAs) into proteins is an essential cellular task. The translational process is monitored by several quality control (QC) mechanisms that recognize defective translation complexes in which ribosomes are stalled on substrate mRNAs. Stalled translation complexes occur when defects in the mRNA template, the translation machinery, or the nascent polypeptide arrest the ribosome during translation elongation or termination. These QC events promote the disassembly of the stalled translation complex and the recycling and/or degradation of the individual mRNA, ribosomal, and/or nascent polypeptide components, thereby clearing the cell of improper translation products and defective components of the translation machinery.

Figure 1.

Multiple cotranslational quality control (QC) pathways monitor the translation process. QC pathways cotranslationally detect and degrade defective nascent polypeptides, ribosomes, and mRNAs.

Figure 2.

Nonsense-mediated mRNA decay (NMD). Premature termination codon (PTC)–containing mRNAs are degraded when a stall in the eRF1/eRF3-dependent translation termination process is detected by Upf and Smg proteins. Some evidence suggests that the resulting truncated protein product can be targeted for ubiquitylation and destroyed by the proteasome in a Upf1- and Cdc48-dependent fashion. m7G refers to the mRNA 7-methyl guanosine cap; AAAAA refers to the poly(A)-tail; Ter indicates a normal termination codon.

Figure 3.

Non-stop mRNA decay (NSD) and protein destruction. mRNAs on which the ribosome reaches the 3′ end without encountering a stop codon are detected by the eRF3-like factor Ski7 and targeted for mRNA decay by the exosome. The stalled ribosome is thought to be released by the Hbs1–Dom34–Rli1 complex. Extraction and destruction of the defective protein products arising from NSD mRNA substrates is mediated by ubiquitin pathway components Ltn1 and Cdc48.

Figure 4.

No-go mRNA decay (NGD) and protein destruction. Diverse mRNA or nascent chain features (*) that result in terminally stalled translation elongation complexes are resolved by a host of mRNA and protein destruction factors. Initial mRNA cleavage by unknown endonuclease(s) allows the alternative ribosome release factors, Hbs1 and Dom34 to mediate ribosomal splitting via Rli1 (ABCE1) and subsequent mRNA decay by RNA exonucleases. The nascent polypeptide is targeted for ubiquitylation by the Ltn1-containing ribosome quality control complex (RQC) and Not4. Hel2 and Asc1 putatively target nascent chains for ubiquitylation before and independent of the RQC.