Initiation of Quality Control during Poly(A) Translation Requires Site-Specific Ribosome Ubiquitination

Summary Diverse cellular stressors have been observed to trigger site-specific ubiquitination on several ribosomal proteins. However, the ubiquitin ligases, biochemical consequences, and physiologic pathways linked to these modifications are not known. Here, we show in mammalian cells that the ubiquitin ligase ZNF598 is required for ribosomes to terminally stall during translation of poly(A) sequences. ZNF598-mediated stalling initiated the ribosome-associated quality control (RQC) pathway for degradation of nascent truncated proteins. Biochemical ubiquitination reactions identified two sites of mono-ubiquitination on the 40S protein eS10 as the primary ribosomal target of ZNF598. Cells lacking ZNF598 activity or containing ubiquitination-resistant eS10 ribosomes failed to stall efficiently on poly(A) sequences. In the absence of stalling, read-through of poly(A) produces a poly-lysine tag, which might alter the localization and solubility of the associated protein. Thus, ribosome ubiquitination can modulate translation elongation and impacts co-translational quality control to minimize production of aberrant proteins.

• Publication year

  2017

• Venue

  Molecules and Cells

• Publication date

  2017-02-16

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1016/j.molcel.2016.11.039PMID 28065601PMCID 5316413
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• The Rqc2/Tae2 subunit of the ribosome-associated quality control (RQC) complex marks ribosome-stalled nascent polypeptide chains for aggregation

  2016cited by this paper
• Distinct types of translation termination generate substrates for ribosome-associated quality control

  2016cited by this paper
• Ribosome-associated protein quality control

  2016cited by this paper
• Codon optimality is a major determinant of mRNA stability.

  2015cited by this paper
• Rapid categorization of natural face images in the infant right hemisphere

  2015cited by this paper
• Translational control by lysine-encoding A-rich sequences

  2015cited by this paper
• Inhibiting K63 Polyubiquitination Abolishes No-Go Type Stalled Translation Surveillance in Saccharomyces cerevisiae

  2015cited by this paper
• The Unfolded Protein Response Triggers Site-Specific Regulatory Ubiquitylation of 40S Ribosomal Proteins.

  2015cited by this paper
• Ribosomes slide on lysine-encoding homopolymeric A stretches

  2015cited by this paper
• Structure and Assembly Pathway of the Ribosome Quality Control Complex

  2015cited by this paper
• Rqc2p and 60S ribosomal subunits mediate mRNA-independent elongation of nascent chains

  2015cited by this paper
• Genome engineering using CRISPR-Cas9 system.

  2015cited by this paper
• Ubiquitination of newly synthesized proteins at the ribosome.

  2015cited by this paper
• C9orf72 repeat expansions cause neurodegeneration in Drosophila through arginine-rich proteins

  2014cited by this paper
• Poly(A)-tail profiling reveals an embryonic switch in translational control

  2014cited by this paper
• Reconstitution of a Minimal Ribosome-Associated Ubiquitination Pathway with Purified Factors

  2014cited by this paper
• Structural basis for translational surveillance by the large ribosomal subunit-associated protein quality control complex

  2014cited by this paper
• Poly-dipeptides encoded by the C9orf72 repeats bind nucleoli, impede RNA biogenesis, and kill cells

  2014cited by this paper
• Release Factor eRF3 Mediates Premature Translation Termination on Polylysine-Stalled Ribosomes in Saccharomyces cerevisiae

  2014cited by this paper
• Translation of CGA codon repeats in yeast involves quality control components and ribosomal protein L1

  2013influential reference
• Enhancement of Heterologous Gene Expression in Flammulina velutipes Using Polycistronic Vectors Containing a Viral 2A Cleavage Sequence

  2013cited by this paper
• Cdc48/p97 promotes degradation of aberrant nascent polypeptides bound to the ribosome

  2013cited by this paper
• Ensembl 2014

  2013cited by this paper
• Cdc48-associated complex bound to 60S particles is required for the clearance of aberrant translation products

  2013cited by this paper
• Listerin-Dependent Nascent Protein Ubiquitination Relies on Ribosome Subunit Dissociation

  2013cited by this paper
• Genome engineering using the CRISPR-Cas9 system

  2013cited by this paper
• Translation drives mRNA quality control

  2012cited by this paper
• Dom34:hbs1 plays a general role in quality-control systems by dissociation of a stalled ribosome at the 3' end of aberrant mRNA.

  2012cited by this paper
• A ribosome-bound quality control complex triggers degradation of nascent peptides and signals translation stress.

  2012influential reference
• Kinetic analysis reveals the ordered coupling of translation termination and ribosome recycling in yeast

  2011cited by this paper
• Dissociation by Pelota, Hbs1 and ABCE1 of mammalian vacant 80S ribosomes and stalled elongation complexes

  2011cited by this paper
• U1 snRNP protects pre-mRNAs from premature cleavage and polyadenylation

  2010cited by this paper
• Dom34:Hbs1 Promotes Subunit Dissociation and Peptidyl-tRNA Drop-Off to Initiate No-Go Decay

  2010cited by this paper
• Receptor for activated C kinase 1 stimulates nascent polypeptide‐dependent translation arrest

  2010cited by this paper
• Role of a ribosome-associated E3 ubiquitin ligase in protein quality control

  2010cited by this paper
• Functional depletion of mahogunin by cytosolically exposed prion protein contributes to neurodegeneration.

  2009cited by this paper
• Electrostatics in the ribosomal tunnel modulate chain elongation rates.

  2008cited by this paper
• Translation of the poly(A) tail plays crucial roles in nonstop mRNA surveillance via translation repression and protein destabilization by proteasome in yeast.

  2007cited by this paper
• Endonucleolytic cleavage of eukaryotic mRNAs with stalls in translation elongation

  2006cited by this paper

• Mitochondrial protein carboxyl-terminal alanine-threonine tailing promotes human glioblastoma growth by regulating mitochondrial function

  2026cites this paper
• Quality control and signaling pathways at stalled ribosomes

  2026cites this paper
• Ribosome-associated quality control of aberrant protein production during amino acid limitation

  2026cites this paper
• Ribosomal Quality Control at the Crossroads of Proteostasis and Diseases: A Guardian and Potential Enabler of Malignant Adaptation

  2026cites this paper
• A giant virus forms a specialized subcellular environment within its amoeba host for efficient translation

  2026influential citation
• The Tor pathway, ribosome concentration, and wobble decoding mediate inhibitory effects of the Leu-Pro CUC-CCG codon pair in Saccharomyces cerevisiae

  2026cites this paper
• Global profiling of nascent chain interactors reveals TRIM25 as a co-translational E3 ubiquitin ligase.

  2026cites this paper
• Yeast elongation factor homolog New1 protects a subset of mRNAs from degradation by no-go decay

  2026cites this paper
• Translational Fidelity Maintained by ZNF598-Dependent Ribosome Resolution Enables Cellular Adaptation to High Energy Demand

  2026influential citation
• Parallel ZNF598 and GIGYF2 pathways mediate conserved collision-dependent mRNA decay with distinct endonucleolytic features

  2026influential citation
• Translatome and translation dynamics analysis of a RiboCancer cell line panel reveals that leukemia-associated Rps15 mutations rewire translation through codon-specific tRNA accommodation defects

  2025cites this paper
• Ribosome-associated proteins: unwRAPping ribosome heterogeneity in the twenty-first century.

  2025cites this paper
• Crosstalk between the ribosome quality control-associated E3 ubiquitin ligases LTN1 and RNF10.

  2025cites this paper
• The integrated stress response regulates 18S nonfunctional rRNA decay in mammals.

  2025cites this paper
• Interpreting ribosome dynamics during mRNA translation

  2025cites this paper
• RNF10 and RIOK3 facilitate 40S ribosomal subunit degradation upon 60S biogenesis disruption or amino acid starvation

  2025cites this paper
• Girolline is a sequence context-selective modulator of eIF5A activity

  2025cites this paper
• tRNA synthetase activity is required for stress granule and P-body assembly

  2025cites this paper
• Pelota-mediated ribosome-associated quality control counteracts aging and age-associated pathologies across species

  2025cites this paper
• Comparative CRISPRi screens reveal a human stem cell dependence on mRNA translation-coupled quality control

  2025influential citation
• Differential regulation of translational stress responses by herpesvirus ubiquitin deconjugases

  2025cites this paper
• Single-protein/RNA imaging reveals ZNF598 as a limiting factor in resolving collided ribosomes

  2025cites this paper
• GCN2 monitors mRNA translation termination.

  2025cites this paper
• GIGYF2: A Multifunctional Regulator at the Crossroads of Gene Expression, mRNA Surveillance, and Human Disease

  2025cites this paper
• Ribosomal protein paralogues in ribosome specialization.

  2025cites this paper
• CRISPR activation of the ribosome-associated quality control factor ASCC3 ameliorates fragile X syndrome phenotypes in mice.

  2025cites this paper
• NEMF-mediated CAT tailing facilitates translocation-associated quality control.

  2025cites this paper
• Causes and consequences of RNA:protein cross-links – lessons from chemotherapy

  2025cites this paper
• Guidelines for minimal reporting requirements, design and interpretation of experiments involving the use of eukaryotic dual gene expression reporters (MINDR)

  2025cites this paper
• Detecting ribosome collisions with differential rRNA fragment analysis in ribosome profiling data

  2025cites this paper
• Lactate Dehydrogenase A Crotonylation and Mono‐Ubiquitination Maintains Vascular Smooth Muscle Cell Growth and Migration and Promotes Neointima Hyperplasia

  2025cites this paper
• Mechanism of chaperone recruitment and retention on mitochondrial precursors

  2025cites this paper
• m6A in the coding sequence: linking deposition, translation, and decay.

  2025cites this paper
• The ribosome ubiquitination code: fine-tuning translation under stress.

  2025cites this paper
• Stalled disomes marked by Hel2-dependent ubiquitin chains undergo Ubp2/Ubp3-mediated deubiquitination upon translational run-off

  2025cites this paper
• TP53-mutant AML with ribosomal gene loss exhibits impaired protein translation and sensitivity to HSP90 inhibition

  2025cites this paper
• GCN1 couples GCN2 to ribosomal state to initiate amino acid response pathway signaling.

  2025cites this paper
• The ribosome-associated quality control factor TCF25 imposes K48 specificity on Listerin-mediated ubiquitination of nascent chains by binding and specifically orienting the acceptor ubiquitin

  2025cites this paper
• Polyubiquitin architecture editing on collided ribosomes maintains persistent RQC activity

  2025cites this paper
• E3 ubiquitin ligase RNF10 promotes dissociation of stalled ribosomes and responds to ribosomal subunit imbalance

  2024cites this paper
• Threonine-rich carboxyl-terminal extension drives aggregation of stalled polypeptides.

  2024cites this paper
• The E3 ligase OsHel2 impedes readthrough of stalled mRNAs to regulate male fertility in thermosensitive genic male sterile rice

  2024cites this paper
• m6A sites in the coding region trigger translation-dependent mRNA decay.

  2024cites this paper
• NEMF-mediated CAT-tailing defines distinct branches of translocation-associated quality control

  2024cites this paper
• Ribosome stalling during c-myc translation presents actionable cancer cell vulnerability

  2024cites this paper
• Mitochondrial Protein Carboxyl-Terminal Alanine-Threonine Tailing Promotes Human Glioblastoma Growth by Regulating Mitochondrial Function

  2024cites this paper
• The ribotoxic stress response drives UV-mediated cell death.

  2024cites this paper
• Dysregulated ribosome quality control in human diseases

  2024cites this paper
• Ribosome specialization in cancer: a spotlight on ribosomal proteins

  2024cites this paper
• Trends and Implications of Ribosome-associated Protein Quality Control in Diseases: A Bibliographic Analysis.

  2024cites this paper
• The integrated stress response in metabolic adaptation

  2024cites this paper
• Chemical inhibition of the integrated stress response impairs the ubiquitin-proteasome system

  2024influential citation
• Ribosomal quality control factors inhibit repeat-associated non-AUG translation from GC-rich repeats

  2024cites this paper
• The ribosome-associated quality control factor TCF25 imposes K48 specificity on Listerin-mediated ubiquitination of nascent chains by binding and specifically orienting the acceptor ubiquitin

  2024cites this paper
• Ribosomal collision is not a prerequisite for ZNF598-mediated ribosome ubiquitination and disassembly of ribosomal complexes by ASCC

  2024cites this paper
• Stalled translation by mitochondrial stress upregulates a CNOT4-ZNF598 ribosomal quality control pathway important for tissue homeostasis

  2024influential citation
• Transcript-specific induction of stop codon readthrough using a CRISPR-dCas13 system

  2024cites this paper
• Polyglutamine-mediated ribotoxicity disrupts proteostasis and stress responses in Huntington’s disease

  2024cites this paper
• The eRF1 degrader SRI-41315 acts as a molecular glue at the ribosomal decoding center

  2024cites this paper
• An E3 ubiquitin ligase CSIT2 controls critical sterility-inducing temperature of thermo-sensitive genic male sterile rice.

  2024cites this paper
• UBXN1 maintains ER proteostasis and represses UPR activation by modulating translation

  2024cites this paper
• Translation of zinc finger domains induces ribosome collision and Znf598-dependent mRNA decay in zebrafish

  2024cites this paper
• Ribosome Quality Control mitigates the cytotoxicity of ribosome collisions induced by 5-Fluorouracil

  2024cites this paper
• Ubiquitin-dependent translation control mechanisms: Degradation and beyond.

  2024cites this paper
• NEMF mutations in mice illustrate how Importin-β specific nuclear transport defects recapitulate neurodegenerative disease hallmarks

  2024cites this paper
• Isoleucine-to-valine substitutions support cellular physiology during isoleucine deprivation

  2024cites this paper
• Mechanisms of translation-coupled quality control.

  2024cites this paper
• Integrated data from R405W desmin knock-in mice highlight alterations of mitochondrial function, protein quality control, and myofibrillar structure in the initial stages of myofibrillar myopathy

  2024cites this paper
• Is there a localized role for translational quality control?

  2023cites this paper
• Tumor necrosis factor mediates USE1-independent FAT10ylation under inflammatory conditions

  2023cites this paper
• Translation‐coupled mRNA quality control mechanisms

  2023cites this paper
• Proteostasis regulation through ribosome quality control and no‐go‐decay

  2023influential citation
• The ribosome quality control factor Asc1 determines the fate of HSP70 mRNA on and off the ribosome

  2023cites this paper
• Ribosomal quality control factors inhibit repeat-associated non-AUG translation from GC-rich repeats

  2023influential citation
• The ribosome-associated protein RACK1 represses Kir4.1 translation in astrocytes and influences neuronal activity

  2023cites this paper
• Noncoding translation mitigation

  2023cites this paper
• Ubiquitinome Profiling Reveals in Vivo UBE2D3 Targets and Implicates UBE2D3 in Protein Quality Control

  2023cites this paper
• Single-molecule imaging reveals distinct elongation and frameshifting dynamics between frames of expanded RNA repeats in C9ORF72-ALS/FTD

  2023cites this paper
• Utilization of Nonstop mRNA to Assess Ribosome-Associated Nascent Polypeptide Chains in Early Topogenesis of Peroxisomal Proteins.

  2023cites this paper
• Imaging spatiotemporal translation regulation in vivo.

  2023cites this paper
• A ubiquitin language communicates ribosomal distress

  2023influential citation
• Recognition of an Ala-rich C-degron by the E3 ligase Pirh2

  2023cites this paper
• Molecular Highway Patrol for Ribosome Collisions

  2023cites this paper
• Run, Ribosome, Run: From Compromised Translation to Human Health

  2023influential citation
• Length-Dependent Translation Efficiency of ER-Destined Proteins

  2023cites this paper
• Molecular basis of eIF5A-dependent CAT tailing in eukaryotic ribosome-associated quality control.

  2023cites this paper
• An E3 ligase network engages GCN1 to promote the degradation of translation factors on stalled ribosomes.

  2023cites this paper
• Remodeling of the Ribosomal Quality Control and Protein Translation by a Viral Ubiquitin Deconjugase

  2023influential citation
• Znf598-mediated Rps10/eS10 ubiquitination contributes to the ribosome ubiquitination dynamics during zebrafish development

  2023cites this paper
• Ending a bad start: Triggers and mechanisms of co-translational protein degradation

  2023cites this paper
• LDHA maintains the growth and migration of vascular smooth muscle cells and promotes neointima formation via crosstalk between K5 crotonylation and K76 mono-ubiquitination

  2023cites this paper
• Transcript-specific induction of stop codon readthrough using CRISPR-dCas13 system

  2023cites this paper
• Remodeling of the ribosomal quality control and integrated stress response by viral ubiquitin deconjugases

  2023influential citation
• Mechanistic insights into the UFM1 E3 ligase complex in ufmylation and ribosome-associated protein quality control

  2023cites this paper
• RPL26/uL24 UFMylation is essential for ribosome-associated quality control at the endoplasmic reticulum

  2023cites this paper
• K6-linked ubiquitylation marks formaldehyde-induced RNA-protein crosslinks for resolution.

  2023cites this paper
• N1-methylpseudouridylation of mRNA causes +1 ribosomal frameshifting

  2023cites this paper
• Massively parallel identification of sequence motifs triggering ribosome-associated mRNA quality control

  2023cites this paper
• Systematic genetic identification of functional domains on collided di‐ribosomes responsible for rescue pathways upon translation arrest in Saccharomyces cerevisiae

  2023cites this paper
• The E3 ubiquitin ligase CSIT1 regulates critical sterility-inducing temperature by ribosome-associated quality control to safeguard two-line hybrid breeding in rice.

  2023cites this paper