. 2020 Feb 20;48(3):1084-1096.
Quality Controls Induced by Aberrant Translation
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Quality Controls Induced by Aberrant Translation
Nucleic Acids Res
Free PMC article
During protein synthesis, translating ribosomes encounter many challenges imposed by various types of defective mRNAs that can lead to reduced cellular fitness and, in some cases, even threaten cell viability. Aberrant translation leads to activation of one of several quality control pathways depending on the nature of the problem. These pathways promote the degradation of the problematic mRNA as well as the incomplete translation product, the nascent polypeptide chain. Many of these quality control systems feature critical roles for specialized regulatory factors that work in concert with conventional factors. This review focuses on the mechanisms used by these quality control pathways to recognize aberrant ribosome stalling and discusses the conservation of these systems.
© The Author(s) 2020. Published by Oxford University Press on behalf of Nucleic Acids Research.
Rescue systems for ribosomes stalled at the 3′ end of nonstop mRNAs. Ribosomes that translate aberrant mRNAs lacking stop codons become stalled at the 3′ end of the mRNA. Left: In prokaryotes, three systems are responsible for rescue of the stalled ribosome. The tmRNA–SmpB complex recruits the highly conserved 3′–5′ RNase R, which is responsible for targeted degradation of nonstop mRNAs (21). Right: In eukaryotes, Dom34 recognizes the empty A-site of ribosomes that are stalled at the 3′ end of nonstop mRNAs. ABCE1-mediated subunit dissociation of the stalled 80S ribosome results in rapid degradation of the released nonstop mRNA by the Ski complex and the exosome. Association with the stalled ribosome facilitates the ATPase activity of the Ski complex and degradation of the nonstop mRNA. Pelota (Dom34)-mediated dissociation of the stalled ribosome and association of the Ski complex–exosome with the ribosome may act cooperatively to ensure processive degradation of the nonstop mRNA from the 3′ end.
trans-translation. During the first step of trans-translation, the 70S ribosome stalls at the 3′-end of a nonstop mRNA. In step 2, EF-Tu delivers Ala–tmRNA–SmpB to the ribosome, where the C-terminal tail of SmpB forms a α-helix in the downstream mRNA channel to form a pre-accommodation state. In step 3, EF-G translocates tmRNA–SmpB from the A-site into the P-site to release the original mRNA and tRNA. In step 4, the nonstop mRNA is switched for the ORF of the tmRNA and translation is resumed. In step 5, translation of the ORF of the tmRNA results in tagging of the aberrant polypeptide with a degradation tag that is recognized by proteases. In step 6, the ribosome is recycled by conventional translation factors.
Quality control systems induced by ribosome stalling. RQC has three steps. Step 1: The abnormal stalled ribosome is recognized and ubiquitinated at one or more specific residues. Step 2: Ribosome ubiquitination induces subunit dissociation, which is a crucial event for Listerin (
S. cerevisiae Ltn1)-dependent ubiquitination of the arrest products on the 60S large ribosomal subunit. The RQT complex is thought to recognize the ubiquitinated stalled ribosome and induce subunit dissociation in yeast. Step 3: Dissociation of the 40S subunits allows binding of 60S RNCs to NEMF (Rqc2), which recruits the E3 ubiquitin ligase Listerin (Ltn1). Subsequently, Listerin ubiquitinates the nascent polypeptide chains, targeting them for degradation. Rqc2 attaches CAT-tails (C-terminal alanyl/threonyl sequences) to stalled polypeptides. The ATPase VCP/p97 (Cdc48) forms a complex with the cofactors UFD1 (Ufd1) and NPLOC4 (Npl4) and unfolds ubiquitinated polypeptides, then extracts the peptidyl-tRNA from the 60S, thereby recruiting it to the 26S proteasome for degradation. Novel roles of ANKZF1 (Vms1)-mediated polypeptide release for proteasomal degradation: Rqc2 catalyzes the C-terminal extension of the stalled tRNA-bound peptides with CAT-tails through a non-canonical elongation reaction without mRNA. CAT-tails functionalize the carboxy termini of stalled polypeptides to drive their degradation on and off the ribosome. Vms1 interacts with the ribosomal 60S subunit to compete with Rqc2 and catalyze peptidyl-tRNA cleavage. Subsequently, tRNA nucleotidyl transferase 1 (TRNT1) is responsible for recycling of ANKZF1-cleaved tRNA fragments.
Ribosome ubiquitination as a trigger of quality control systems induced by ribosome stalling. Left: In RQC, the critical E3 ubiquitin ligase Hel2 and its mammalian homolog ZNF598 recognize disomes containing colliding ribosomes in the rotated state (73,79), leading to ubiquitination of uS10 in yeast and uS10, eS10, and uS3 in mammals. Right: In 18S NRD, non-functional 80S ribosomes containing the A1492C mutation in the decoding center stall due to decoding failures and are sequentially ubiquitinated at the K212 residue of uS3. Mag2 monoubiquitinates uS3 at K212, followed by Hel2-mediated polyubiquitination. Subsequently, the Ski2-like RNA helicase Slh1 in the RQT complex stimulates subunit dissociation to promote Xrn1-dependent degradation of the non-functional 18S rRNA in the 40S subunit (100). In these quality control systems, the ribosome is stalled at the specific conformation, and the specific E3 ligases recognize and ubiquitinate particular sites to induce the subsequent quality control steps.
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Proteasome Endopeptidase Complex / metabolism
RNA, Messenger / metabolism
RNA, Ribosomal / metabolism
Proteasome Endopeptidase Complex