Detection and Degradation of Stalled Nascent Chains via Ribosome-Associated Quality Control

Sitron, Cole S.; Brandman, Onn

doi:10.1146/annurev-biochem-013118-110729

Cited by 61 publications

(45 citation statements)

References 146 publications

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“…Eukaryotes have several mechanisms that monitor the status of the general translational activity, including avail ability of amino acids, fidelity of the co translational folding, and correct addressing of protein products. They are also involved in the translation quality control of indi vidual transcripts by each ribosome [6,286]. At the end of the last century, it was shown that mammalian cells exposed to anisomycin or some other elongation inhibitors activate a special program called the ribotoxic stress response [287].…”

Section: Ribotoxic Stress and Translation Related Stress Responsesmentioning

confidence: 99%

“…The authors showed that the collided ribosomes orchestrate three different molecular pathways that have been previously considered independent. In the case of a single collision, the mecha nisms of ribosomal quality control (RQC) are induced [6,286], leading to the disassembly of the stalled elongation complex without triggering the general response. As the number of such events increases (for example, during amino acid starvation), the binding of GCN1 and GCN20 proteins and the MAP3K cascade kinase ZAK to the colliding ribosomes activates GCN2 kinase, which phosphorylates eIF2 (see above).…”

Section: Ribotoxic Stress and Translation Related Stress Responsesmentioning

confidence: 99%

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A Quick Guide to Small-Molecule Inhibitors of Eukaryotic Protein Synthesis

Dmitriev

Vladimirov

Lashkevich

2020

Biochemistry Moscow

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Eukaryotic ribosome and cap-dependent translation are attractive targets in the antitumor, antiviral, anti-inflammatory, and antiparasitic therapies. Currently, a broad array of small-molecule drugs is known that specifically inhibit protein synthesis in eukaryotic cells. Many of them are well-studied ribosome-targeting antibiotics that block translocation, the peptidyl transferase center or the polypeptide exit tunnel, modulate the binding of translation machinery components to the ribosome, and induce miscoding, premature termination or stop codon readthrough. Such inhibitors are widely used as anticancer, anthelmintic and antifungal agents in medicine, as well as fungicides in agriculture. Chemicals that affect the accuracy of stop codon recognition are promising drugs for the nonsense suppression therapy of hereditary diseases and restoration of tumor suppressor function in cancer cells. Other compounds inhibit aminoacyl-tRNA synthetases, translation factors, and components of translation-associated signaling pathways, including mTOR kinase. Some of them have antidepressant, immunosuppressive and geroprotective properties. Translation inhibitors are also used in research for gene expression analysis by ribosome profiling, as well as in cell culture techniques. In this article, we review well-studied and less known inhibitors of eukaryotic protein synthesis (with the exception of mitochondrial and plastid translation) classified by their targets and briefly describe the action mechanisms of these compounds. We also present a continuously updated database (http://eupsic.belozersky.msu.ru/) that currently contains information on 370 inhibitors of eukaryotic protein synthesis.

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Section: Ribotoxic Stress and Translation Related Stress Responsesmentioning

confidence: 99%

Section: Ribotoxic Stress and Translation Related Stress Responsesmentioning

confidence: 99%

A Quick Guide to Small-Molecule Inhibitors of Eukaryotic Protein Synthesis

Dmitriev

Vladimirov

Lashkevich

2020

Biochemistry Moscow

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“…Recent discoveries have revealed the important regulatory role RQC plays during host translation especially under conditions the elevate the frequency of ribosome collisions(Joazeiro 2019). A large number of evolutionarily conserved proteins coordinate RQC within a signaling hierarchy(Sitron and Brandman 2020). The physiological role for RQC factors in maintaining ribosome availability is exemplified by Pelota, which assists in recycling stalled ribosomal subunits(Pisareva et al 2011; Guydosh and Green 2014), and where loss-of-function results in diminished translation of globin mRNAs in blood cells (Mills et al 2016).…”

Section: Discussionmentioning

confidence: 99%

Ribosome quality control activity potentiates vaccinia virus protein synthesis during infection

Sundaramoorthy¹,

Ryan²,

Fulzele³

et al. 2020

Preprint

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Ribosomes are highly abundant cellular machines that perform the essential task of translating the genetic code into proteins. Cellular translation activity is finely tuned and proteostasis insults, such as those incurred upon viral infection, activate stress signaling pathways that result in translation reprogramming. Viral infection selectively shuts down host mRNA while redistributing ribosomes for selective translation of viral mRNAs. The intricacies of this selective ribosome shuffle from host to viral mRNAs are poorly understood. Here, we uncover a role for the ribosome associated quality control (RQC) factor ZNF598, a sensor for collided ribosomes, as a critical factor for vaccinia virus mRNA translation. Collided ribosomes are sensed by ZNF598, which ubiquitylates 40S subunit proteins uS10 and eS10 and thereby initiates RQC-dependent nascent chain degradation and ribosome recycling. We show that vaccinia infection in human cells enhances uS10 ubiquitylation indicating an increased burden on RQC pathways during viral propagation. Consistent with an increased RQC demand, we demonstrate that vaccinia virus replication is impaired in cells which either lack ZNF598 or contain a ubiquitylation deficient version of uS10. Using SILAC-based proteomics and concurrent RNAseq analysis, we determine that host translation of vaccinia virus mRNAs is compromised in cells that lack RQC activity as compared to control cells whereas there was little evidence of differences in host or viral transcription. Additionally, vaccinia virus infection resulted in a loss of cellular RQC activity, suggesting that ribosomes engaged in viral protein production recruit ZNF598 away from its function in host translation. Thus, co-option of ZNF598 by vaccinia virus plays a critical role in translational reprogramming that is needed for optimal viral propagation.

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“…Translation of faulty mRNAs bearing no stop codon (NS mRNAs) represents a major trigger of ribosome stalling both in the cytosol and on the ER membrane (Brandman and Hegde, 2016;Joazeiro, 2017Joazeiro, , 2019Sitron and Brandman, 2020). NS mRNAs are frequently generated in eukaryotic cells due to genetic mutations or premature polyadenylation (Arthur et al, 2015), resulting in a poly-A-containing open reading frame that can stall ribosomes during translation (Arthur et al, 2015;Juszkiewicz and Hegde, 2017).…”

Section: Scenarios Of Translocon Clogging During Cotranslational Protmentioning

confidence: 99%

“…Studies on ribosome stalling in the cytosol have established a PQC pathway named ribosome-associated quality control (RQC) (Brandman and Hegde, 2016;Joazeiro, 2017;Sitron and Brandman, 2020). In this process, a collection of cellular factors coordinately sense translation stalling, rescue stalled ribosomes, and degrade arrested polypeptides together with defective mRNAs.…”

Section: Ribosome Stalling and Ribosome-associated Quality Controlmentioning

confidence: 99%

Clearing Traffic Jams During Protein Translocation Across Membranes

Wang

2021

Front. Cell Dev. Biol.

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Protein translocation across membranes is a critical facet of protein biogenesis in compartmentalized cells as proteins synthesized in the cytoplasm often need to traverse across lipid bilayers via proteinaceous channels to reach their final destinations. It is well established that protein biogenesis is tightly linked to various protein quality control processes, which monitor errors in protein folding, modification, and localization. However, little is known about how cells cope with translocation defective polypeptides that clog translocation channels (translocons) during protein translocation. This review summarizes recent studies, which collectively reveal a set of translocon-associated quality control strategies for eliminating polypeptides stuck in protein-conducting channels in the endoplasmic reticulum and mitochondria.

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Detection and Degradation of Stalled Nascent Chains via Ribosome-Associated Quality Control

Cited by 61 publications

References 146 publications

A Quick Guide to Small-Molecule Inhibitors of Eukaryotic Protein Synthesis

A Quick Guide to Small-Molecule Inhibitors of Eukaryotic Protein Synthesis

Ribosome quality control activity potentiates vaccinia virus protein synthesis during infection

Clearing Traffic Jams During Protein Translocation Across Membranes

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