Journal articles on the topic 'Nascent polypeptide-Associated control'
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1
Gamerdinger, Martin. "Protein quality control at the ribosome: focus on RAC, NAC and RQC." Essays in Biochemistry 60, no. 2 (October 15, 2016): 203–12. http://dx.doi.org/10.1042/ebc20160011.
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The biogenesis of new polypeptides by ribosomes and their subsequent correct folding and localization to the appropriate cellular compartments are essential key processes to maintain protein homoeostasis. These complex mechanisms are governed by a repertoire of protein biogenesis factors that directly bind to the ribosome and chaperone nascent polypeptide chains as soon as they emerge from the ribosomal tunnel exit. This nascent chain ‘welcoming committee’ regulates multiple co-translational processes including protein modifications, folding, targeting and degradation. Acting at the front of the protein production line, these ribosome-associated protein biogenesis factors lead the way in the cellular proteostasis network to ensure proteome integrity. In this article, I focus on three different systems in eukaryotes that are critical for the maintenance of protein homoeostasis by controlling the birth, life and death of nascent polypeptide chains.
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Spreter, Thomas, Markus Pech, and Birgitta Beatrix. "The Crystal Structure of Archaeal Nascent Polypeptide-associated Complex (NAC) Reveals a Unique Fold and the Presence of a Ubiquitin-associated Domain." Journal of Biological Chemistry 280, no. 16 (January 22, 2005): 15849–54. http://dx.doi.org/10.1074/jbc.m500160200.
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Nascent polypeptide-associated complex (NAC) was identified in eukaryotes as the first cytosolic factor that contacts the nascent polypeptide chain emerging from the ribosome. NAC is highly conserved from yeast to humans. Mutations in NAC cause severe embryonically lethal phenotypes in mice,Drosophila,andCaenorhabditis elegans.NAC was suggested to protect the nascent chain from inappropriate early interactions with cytosolic factors. Eukaryotic NAC is a heterodimer with two subunits sharing substantial homology with each other. All sequenced archaebacterial genomes exhibit only one gene homologous to the NAC subunits. Here we present the first archaebacterial NAC homolog. It forms a homodimer, and as eukaryotic NAC it is associated with ribosomes and contacts the emerging nascent chain on the ribosome. We present the first crystal structure of a NAC protein revealing two structural features: (i) a novel unique protein fold that mediates dimerization of the complex, and (ii) a ubiquitin-associated domain that suggests a yet unidentified role for NAC in the cellular protein quality control system via the ubiquitination pathway. Based on the presented structure we propose a model for the eukaryotic heterodimeric NAC domain.
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Yang, Chien-I., Hao-Hsuan Hsieh, and Shu-ou Shan. "Timing and specificity of cotranslational nascent protein modification in bacteria." Proceedings of the National Academy of Sciences 116, no. 46 (October 30, 2019): 23050–60. http://dx.doi.org/10.1073/pnas.1912264116.
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The nascent polypeptide exit site of the ribosome is a crowded environment where multiple ribosome-associated protein biogenesis factors (RPBs) compete for the nascent polypeptide to influence their localization, folding, or quality control. Here we address how N-terminal methionine excision (NME), a ubiquitous process crucial for the maturation of over 50% of the bacterial proteome, occurs in a timely and selective manner in this crowded environment. In bacteria, NME is mediated by 2 essential enzymes, peptide deformylase (PDF) and methionine aminopeptidase (MAP). We show that the reaction of MAP on ribosome-bound nascent chains approaches diffusion-limited rates, allowing immediate methionine excision of optimal substrates after deformylation. Specificity is achieved by kinetic competition of NME with translation elongation and by regulation from other RPBs, which selectively narrow the processing time window for suboptimal substrates. A mathematical model derived from the data accurately predicts cotranslational NME efficiency in the cytosol. Our results demonstrate how a fundamental enzymatic activity is reshaped by its associated macromolecular environment to optimize both efficiency and selectivity, and provides a platform to study other cotranslational protein biogenesis pathways.
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Karamyshev, Andrey L., Elena B. Tikhonova, and Zemfira N. Karamysheva. "Translational Control of Secretory Proteins in Health and Disease." International Journal of Molecular Sciences 21, no. 7 (April 6, 2020): 2538. http://dx.doi.org/10.3390/ijms21072538.
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Secretory proteins are synthesized in a form of precursors with additional sequences at their N-terminal ends called signal peptides. The signal peptides are recognized co-translationally by signal recognition particle (SRP). This interaction leads to targeting to the endoplasmic reticulum (ER) membrane and translocation of the nascent chains into the ER lumen. It was demonstrated recently that in addition to a targeting function, SRP has a novel role in protection of secretory protein mRNAs from degradation. It was also found that the quality of secretory proteins is controlled by the recently discovered Regulation of Aberrant Protein Production (RAPP) pathway. RAPP monitors interactions of polypeptide nascent chains during their synthesis on the ribosomes and specifically degrades their mRNAs if these interactions are abolished due to mutations in the nascent chains or defects in the targeting factor. It was demonstrated that pathological RAPP activation is one of the molecular mechanisms of human diseases associated with defects in the secretory proteins. In this review, we discuss recent progress in understanding of translational control of secretory protein biogenesis on the ribosome and pathological consequences of its dysregulation in human diseases.
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Jomaa, Ahmad, Martin Gamerdinger, Hao-Hsuan Hsieh, Annalena Wallisch, Viswanathan Chandrasekaran, Zeynel Ulusoy, Alain Scaiola, et al. "Mechanism of signal sequence handover from NAC to SRP on ribosomes during ER-protein targeting." Science 375, no. 6583 (February 25, 2022): 839–44. http://dx.doi.org/10.1126/science.abl6459.
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The nascent polypeptide–associated complex (NAC) interacts with newly synthesized proteins at the ribosomal tunnel exit and competes with the signal recognition particle (SRP) to prevent mistargeting of cytosolic and mitochondrial polypeptides to the endoplasmic reticulum (ER). How NAC antagonizes SRP and how this is overcome by ER targeting signals are unknown. Here, we found that NAC uses two domains with opposing effects to control SRP access. The core globular domain prevented SRP from binding to signal-less ribosomes, whereas a flexibly attached domain transiently captured SRP to permit scanning of nascent chains. The emergence of an ER-targeting signal destabilized NAC’s globular domain and facilitated SRP access to the nascent chain. These findings elucidate how NAC hands over the signal sequence to SRP and imparts specificity of protein localization.
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Yotov, Wagner V., Alain Moreau, and René St-Arnaud. "The Alpha Chain of the Nascent Polypeptide-Associated Complex Functions as a Transcriptional Coactivator." Molecular and Cellular Biology 18, no. 3 (March 1, 1998): 1303–11. http://dx.doi.org/10.1128/mcb.18.3.1303.
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ABSTRACT We report the characterization of clone 1.9.2, a gene expressed in mineralizing osteoblasts. Remarkably, clone 1.9.2 is the murine homolog of the alpha chain of the nascent polypeptide-associated complex (α-NAC). Based on sequence similarities between α-NAC/1.9.2 and transcriptional regulatory proteins and the fact that the heterodimerization partner of α-NAC was identified as the transcription factor BTF3b (B. Wiedmann, H. Sakai, T. A. Davis, and M. Wiedmann, Nature 370:434–440, 1994), we investigated a putative role for α-NAC/1.9.2 in transcriptional control. The α-NAC/1.9.2 protein potentiated by 10-fold the activity of the chimeric activator GAL4/VP-16 in vivo. The potentiation was shown to be mediated at the level of gene transcription, because α-NAC/1.9.2 increased GAL4/VP-16-mediated mRNA synthesis without affecting the half-life of the GAL4/VP-16 fusion protein. Moreover, the interaction of α-NAC/1.9.2 with a transcriptionally defective mutant of GAL4/VP-16 was severely compromised. Specific protein-protein interactions between α-NAC/1.9.2 and GAL4/VP-16 were demonstrated by gel retardation, affinity chromatography, and protein blotting assays, while interactions with TATA box-binding protein (TBP) were detected by immunoprecipitation, affinity chromatography, and protein blotting assays. Based on these interactions that define the coactivator class of proteins, we conclude that the α-NAC/1.9.2 gene product functions as a transcriptional coactivator.
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Koplin, Ansgar, Steffen Preissler, Yulia Ilina, Miriam Koch, Annika Scior, Marc Erhardt, and Elke Deuerling. "A dual function for chaperones SSB–RAC and the NAC nascent polypeptide–associated complex on ribosomes." Journal of Cell Biology 189, no. 1 (April 5, 2010): 57–68. http://dx.doi.org/10.1083/jcb.200910074.
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The yeast Hsp70/40 system SSB–RAC (stress 70 B–ribosome-associated complex) binds to ribosomes and contacts nascent polypeptides to assist cotranslational folding. In this study, we demonstrate that nascent polypeptide–associated complex (NAC), another ribosome-tethered system, is functionally connected to SSB–RAC and the cytosolic Hsp70 network. Simultaneous deletions of genes encoding NAC and SSB caused conditional loss of cell viability under protein-folding stress conditions. Furthermore, NAC mutations revealed genetic interaction with a deletion of Sse1, a nucleotide exchange factor regulating the cytosolic Hsp70 network. Cells lacking SSB or Sse1 showed protein aggregation, which is enhanced by additional loss of NAC; however, these mutants differ in their potential client repertoire. Aggregation of ribosomal proteins and biogenesis factors accompanied by a pronounced deficiency in ribosomal particles and translating ribosomes only occurs in ssbΔ and nacΔssbΔ cells, suggesting that SSB and NAC control ribosome biogenesis. Thus, SSB–RAC and NAC assist protein folding and likewise have important functions for regulation of ribosome levels. These findings emphasize the concept that ribosome production is coordinated with the protein-folding capacity of ribosome-associated chaperones.
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Rahul, Pachal, and Dr Medda A. Satyaraj. "Ribosome Associated Protein Quality Control: Mechanism and Function." International Journal for Research in Applied Sciences and Biotechnology 9, no. 1 (February 11, 2022): 118–26. http://dx.doi.org/10.31033/ijrasb.9.1.14.
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Due to numerous reasons, including faulty m RNA, insufficient availability of charged t RNA, genetic errors, ribosomes are failed to synthesize protein sometimes. All organisms develop their machinery to recognize stalled ribosomes. Stalled ribosomes, results in the production of a truncated polypeptide which can affect cells. So, they must be eliminated, by mechanisms known as Ribosome-associated protein quality control (RQC). E3 ubiquitin ligase Ltn1 in RQC promotes clearance of 60S subunit and targets aberrant nascent polypeptides for proteasomal degradation. In eukaryotes, RQC facilitates the ribosomal rescue, where staled m RNAs release and allow to degrade and ribosomal subunits are to be recycled for further use. Ribosome-associated protein quality control in yeast is accomplished by Hel2-dependent ubiquitination of uS10 and RQC-trigger (RQT) complex. RQC in a mammal is done by ZNF598-dependent ubiquitination of collided ribosomes, which also activates signal integrator 3, a component of the ASCC complex. Human RQT (h RQT) is made up of ASCC3, ASCC2, TRIP4, which are orthologs of RNA helicase Slh1, ubiquitin-binding protein Cue3, and ykR023W protein respectively. Ubiquitin-binding activity and ATPase activity of ASCC2 and ASCC3 respectively, are important for RQC. So, it is obvious that the h RQT complex recognizes the ubiquitinated defective ribosome and induces subunit dissociation for RQC. Biogenesis of new polypeptide, folding, correct localization are the fundamental processes to maintain proteostasis, which involve various factors directly attached with ribosomes and chaperones. Ribosome-associated protein biogenesis factors mediate the cellular proteostasis network to form integrity.
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Yadav, Kusum, Anurag Yadav, Priyanka Vashistha, Veda P. Pandey, and Upendra N. Dwivedi. "Protein Misfolding Diseases and Therapeutic Approaches." Current Protein & Peptide Science 20, no. 12 (December 16, 2019): 1226–45. http://dx.doi.org/10.2174/1389203720666190610092840.
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Protein folding is the process by which a polypeptide chain acquires its functional, native 3D structure. Protein misfolding, on the other hand, is a process in which protein fails to fold into its native functional conformation. This misfolding of proteins may lead to precipitation of a number of serious diseases such as Cystic Fibrosis (CF), Alzheimer’s Disease (AD), Parkinson’s Disease (PD), and Amyotrophic Lateral Sclerosis (ALS) etc. Protein Quality-control (PQC) systems, consisting of molecular chaperones, proteases and regulatory factors, help in protein folding and prevent its aggregation. At the same time, PQC systems also do sorting and removal of improperly folded polypeptides. Among the major types of PQC systems involved in protein homeostasis are cytosolic, Endoplasmic Reticulum (ER) and mitochondrial ones. The cytosol PQC system includes a large number of component chaperones, such as Nascent-polypeptide-associated Complex (NAC), Hsp40, Hsp70, prefoldin and T Complex Protein-1 (TCP-1) Ring Complex (TRiC). Protein misfolding diseases caused due to defective cytosolic PQC system include diseases involving keratin/collagen proteins, cardiomyopathies, phenylketonuria, PD and ALS. The components of PQC system of Endoplasmic Reticulum (ER) include Binding immunoglobulin Protein (BiP), Calnexin (CNX), Calreticulin (CRT), Glucose-regulated Protein GRP94, the thiol-disulphide oxidoreductases, Protein Disulphide Isomerase (PDI) and ERp57. ER-linked misfolding diseases include CF and Familial Neurohypophyseal Diabetes Insipidus (FNDI). The components of mitochondrial PQC system include mitochondrial chaperones such as the Hsp70, the Hsp60/Hsp10 and a set of proteases having AAA+ domains similar to the proteasome that are situated in the matrix or the inner membrane. Protein misfolding diseases caused due to defective mitochondrial PQC system include medium-chain acyl-CoA dehydrogenase (MCAD)/Short-chain Acyl-CoA Dehydrogenase (SCAD) deficiency diseases, hereditary spastic paraplegia. Among therapeutic approaches towards the treatment of various protein misfolding diseases, chaperones have been suggested as potential therapeutic molecules for target based treatment. Chaperones have been advantageous because of their efficient entry and distribution inside the cells, including specific cellular compartments, in therapeutic concentrations. Based on the chemical nature of the chaperones used for therapeutic purposes, molecular, chemical and pharmacological classes of chaperones have been discussed.
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Requião, Rodrigo D., Géssica C. Barros, Tatiana Domitrovic, and Fernando L. Palhano. "Influence of nascent polypeptide positive charges on translation dynamics." Biochemical Journal 477, no. 15 (August 14, 2020): 2921–34. http://dx.doi.org/10.1042/bcj20200303.
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Protein segments with a high concentration of positively charged amino acid residues are often used in reporter constructs designed to activate ribosomal mRNA/protein decay pathways, such as those involving nonstop mRNA decay (NSD), no-go mRNA decay (NGD) and the ribosome quality control (RQC) complex. It has been proposed that the electrostatic interaction of the positively charged nascent peptide with the negatively charged ribosomal exit tunnel leads to translation arrest. When stalled long enough, the translation process is terminated with the degradation of the transcript and an incomplete protein. Although early experiments made a strong argument for this mechanism, other features associated with positively charged reporters, such as codon bias and mRNA and protein structure, have emerged as potent inducers of ribosome stalling. We carefully reviewed the published data on the protein and mRNA expression of artificial constructs with diverse compositions as assessed in different organisms. We concluded that, although polybasic sequences generally lead to lower translation efficiency, it appears that an aggravating factor, such as a nonoptimal codon composition, is necessary to cause translation termination events.
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Panasenko, Olesya, Emilie Landrieux, Marc Feuermann, Andrija Finka, Nicole Paquet, and Martine A. Collart. "The Yeast Ccr4-Not Complex Controls Ubiquitination of the Nascent-associated Polypeptide (NAC-EGD) Complex." Journal of Biological Chemistry 281, no. 42 (August 22, 2006): 31389–98. http://dx.doi.org/10.1074/jbc.m604986200.
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Panasenko, Olesya, Emilie Landrieux, Marc Feuermann, Andrija Finka, Nicole Paquet, and Martine A. Collart. "The Yeast Ccr4-Not Complex Controls Ubiquitination of the Nascent-associated Polypeptide (NAC-EGD) Complex." Journal of Biological Chemistry 281, no. 42 (October 2006): 31389–98. http://dx.doi.org/10.1016/s0021-9258(19)84051-6.
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Ivessa, NE, C. De Lemos-Chiarandini, YS Tsao, A. Takatsuki, M. Adesnik, DD Sabatini, and G. Kreibich. "O-glycosylation of intact and truncated ribophorins in brefeldin A-treated cells: newly synthesized intact ribophorins are only transiently accessible to the relocated glycosyltransferases." Journal of Cell Biology 117, no. 5 (June 1, 1992): 949–58. http://dx.doi.org/10.1083/jcb.117.5.949.
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Ribophorins I and II are type I transmembrane glycoproteins of the ER that are segregated to the rough domains of this organelle. Both ribophorins appear to be part of the translocation apparatus for nascent polypeptides that is associated with membrane-bound ribosomes and participate in the formation of a proteinaceous network within the ER membrane that also includes other components of the translocation apparatus. The ribophorins are both highly stable proteins that lack O-linked sugars but each contains one high mannose N-linked oligosaccharide that remains endo H sensitive throughout their lifetimes. We have previously shown (Tsao, Y. S., N. E. Ivessa, M. Adesnik, D. D. Sabatini, and G. Kreibich. 1992. J. Cell Biol. 116:57-67) that a COOH-terminally truncated variant of ribophorin I that contains only the first 332 amino acids of the luminal domain (RI332), when synthesized in permanent transformants of HeLa cells, undergoes a rapid degradation with biphasic kinetics in the ER itself and in a second, as yet unidentified nonlysosomal pre-Golgi compartment. We now show that in cells treated with brefeldin A (BFA) RI332 molecules undergo rapid O-glycosylation in a multistep process that involves the sequential addition of N-acetylgalactosamine, galactose, and terminal sialic acid residues. Addition of O-linked sugars affected all newly synthesized RI332 molecules and was completed soon after synthesis with a half time of about 10 min. In the same cells, intact ribophorins I and II also underwent O-linked glycosylation in the presence of BFA, but these molecules were modified only during a short time period immediately after their synthesis was completed, and the modification affected only a fraction of the newly synthesized polypeptides. More important, these molecules synthesized before the addition of BFA were not modified by O-glycosylation. The same is true for ribophorin I when overexpressed in HeLa cells although it is significantly less stable than the native polypeptide in control cells. We, therefore, conclude that soon after their synthesis, ribophorins lose their susceptibility to the relocated Golgi enzymes that effect the O-glycosylation, most likely as a consequence of a conformational change in the ribophorins that occurs during their maturation, although it cannot be excluded that rapid integration of these molecules into a supramolecular complex in the ER membrane leads to their inaccessibility to these enzymes.
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Berkholz, Janine, Andreas Zakrzewicz, and Barbara Munz. "skNAC depletion stimulates myoblast migration and perturbs sarcomerogenesis by enhancing calpain 1 and 3 activity." Biochemical Journal 453, no. 2 (June 28, 2013): 303–10. http://dx.doi.org/10.1042/bj20130195.
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skNAC (skeletal and heart muscle specific variant of nascent polypeptide-associated complex α) is a skeletal and heart muscle-specific protein known to be involved in the regulation of sarcomerogenesis. The respective mechanism, however, is largely unknown. In the present paper, we demonstrate that skNAC regulates calpain activity. Specifically, we show that inhibition of skNAC gene expression leads to enhanced, and overexpression of the skNAC gene to repressed, activity of calpain 1 and, to a lesser extent, calpain 3 in myoblasts. In skNAC siRNA-treated cells, enhanced calpain activity is associated with increased migration rates, as well as with perturbed sarcomere architecture. Treatment of skNAC-knockdown cells with the calpain inhibitor ALLN (N-acetyl-leucyl-leucyl-norleucinal) reverts both the positive effect on myoblast migration and the negative effect on sarcomere architecture. Taken together, our data suggest that skNAC controls myoblast migration and sarcomere architecture in a calpain-dependent manner.
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Zheng, Alice J. L., Aikaterini Thermou, Chrysoula Daskalogianni, Laurence Malbert-Colas, Konstantinos Karakostis, Ronan Le Sénéchal, Van Trang Dinh, et al. "The nascent polypeptide-associated complex (NAC) controls translation initiation in cis by recruiting nucleolin to the encoding mRNA." Nucleic Acids Research, September 15, 2022. http://dx.doi.org/10.1093/nar/gkac751.
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Abstract Protein aggregates and abnormal proteins are toxic and associated with neurodegenerative diseases. There are several mechanisms to help cells get rid of aggregates but little is known on how cells prevent aggregate-prone proteins from being synthesised. The EBNA1 of the Epstein-Barr virus (EBV) evades the immune system by suppressing its own mRNA translation initiation in order to minimize the production of antigenic peptides for the major histocompatibility (MHC) class I pathway. Here we show that the emerging peptide of the disordered glycine–alanine repeat (GAr) within EBNA1 dislodges the nascent polypeptide-associated complex (NAC) from the ribosome. This results in the recruitment of nucleolin to the GAr-encoding mRNA and suppression of mRNA translation initiation in cis. Suppressing NAC alpha (NACA) expression prevents nucleolin from binding to the GAr mRNA and overcomes GAr-mediated translation inhibition. Taken together, these observations suggest that EBNA1 exploits a nascent protein quality control pathway to regulate its own rate of synthesis that is based on sensing the nascent GAr peptide by NAC followed by the recruitment of nucleolin to the GAr-encoding RNA sequence.
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Osuna, Beatriz A., Conor J. Howard, Subheksha KC, Adam Frost, and David E. Weinberg. "In vitro analysis of RQC activities provides insights into the mechanism and function of CAT tailing." eLife 6 (July 18, 2017). http://dx.doi.org/10.7554/elife.27949.
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Ribosomes can stall during translation due to defects in the mRNA template or translation machinery, leading to the production of incomplete proteins. The Ribosome-associated Quality control Complex (RQC) engages stalled ribosomes and targets nascent polypeptides for proteasomal degradation. However, how each RQC component contributes to this process remains unclear. Here we demonstrate that key RQC activities—Ltn1p-dependent ubiquitination and Rqc2p-mediated Carboxy-terminal Alanine and Threonine (CAT) tail elongation—can be recapitulated in vitro with a yeast cell-free system. Using this approach, we determined that CAT tailing is mechanistically distinct from canonical translation, that Ltn1p-mediated ubiquitination depends on the poorly characterized RQC component Rqc1p, and that the process of CAT tailing enables robust ubiquitination of the nascent polypeptide. These findings establish a novel system to study the RQC and provide a framework for understanding how RQC factors coordinate their activities to facilitate clearance of incompletely synthesized proteins.
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Yonashiro, Ryo, Erich B. Tahara, Mario H. Bengtson, Maria Khokhrina, Holger Lorenz, Kai-Chun Chen, Yu Kigoshi-Tansho, et al. "The Rqc2/Tae2 subunit of the ribosome-associated quality control (RQC) complex marks ribosome-stalled nascent polypeptide chains for aggregation." eLife 5 (March 4, 2016). http://dx.doi.org/10.7554/elife.11794.
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Ribosome stalling during translation can potentially be harmful, and is surveyed by a conserved quality control pathway that targets the associated mRNA and nascent polypeptide chain (NC). In this pathway, the ribosome-associated quality control (RQC) complex promotes the ubiquitylation and degradation of NCs remaining stalled in the 60S subunit. NC stalling is recognized by the Rqc2/Tae2 RQC subunit, which also stabilizes binding of the E3 ligase, Listerin/Ltn1. Additionally, Rqc2 modifies stalled NCs with a carboxy-terminal, Ala- and Thr-containing extension—the 'CAT tail'. However, the function of CAT tails and fate of CAT tail-modified ('CATylated') NCs has remained unknown. Here we show that CATylation mediates formation of detergent-insoluble NC aggregates. CATylation and aggregation of NCs could be observed either by inactivating Ltn1 or by analyzing NCs with limited ubiquitylation potential, suggesting that inefficient targeting by Ltn1 favors the Rqc2-mediated reaction. These findings uncover a translational stalling-dependent protein aggregation mechanism, and provide evidence that proteins can become specifically marked for aggregation.
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Hildebrandt, Andrea, Mirko Brüggemann, Cornelia Rücklé, Susan Boerner, Jan B. Heidelberger, Anke Busch, Heike Hänel, et al. "The RNA-binding ubiquitin ligase MKRN1 functions in ribosome-associated quality control of poly(A) translation." Genome Biology 20, no. 1 (October 22, 2019). http://dx.doi.org/10.1186/s13059-019-1814-0.
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Abstract Background Cells have evolved quality control mechanisms to ensure protein homeostasis by detecting and degrading aberrant mRNAs and proteins. A common source of aberrant mRNAs is premature polyadenylation, which can result in non-functional protein products. Translating ribosomes that encounter poly(A) sequences are terminally stalled, followed by ribosome recycling and decay of the truncated nascent polypeptide via ribosome-associated quality control. Results Here, we demonstrate that the conserved RNA-binding E3 ubiquitin ligase Makorin Ring Finger Protein 1 (MKRN1) promotes ribosome stalling at poly(A) sequences during ribosome-associated quality control. We show that MKRN1 directly binds to the cytoplasmic poly(A)-binding protein (PABPC1) and associates with polysomes. MKRN1 is positioned upstream of poly(A) tails in mRNAs in a PABPC1-dependent manner. Ubiquitin remnant profiling and in vitro ubiquitylation assays uncover PABPC1 and ribosomal protein RPS10 as direct ubiquitylation substrates of MKRN1. Conclusions We propose that MKRN1 mediates the recognition of poly(A) tails to prevent the production of erroneous proteins from prematurely polyadenylated transcripts, thereby maintaining proteome integrity.
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Eisenack, Tom Joshua, and Débora Broch Trentini. "Ending a bad start: Triggers and mechanisms of co-translational protein degradation." Frontiers in Molecular Biosciences 9 (January 4, 2023). http://dx.doi.org/10.3389/fmolb.2022.1089825.
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Proteins are versatile molecular machines that control and execute virtually all cellular processes. They are synthesized in a multilayered process requiring transfer of information from DNA to RNA and finally into polypeptide, with many opportunities for error. In addition, nascent proteins must successfully navigate a complex folding-energy landscape, in which their functional native state represents one of many possible outcomes. Consequently, newly synthesized proteins are at increased risk of misfolding and toxic aggregation. To maintain proteostasis–the state of proteome balance–cells employ a plethora of molecular chaperones that guide proteins along a productive folding pathway and quality control factors that direct misfolded species for degradation. Achieving the correct balance between folding and degradation therefore represents a fundamental task for the proteostasis network. While many chaperones act co-translationally, protein quality control is generally considered to be a post-translational process, as the majority of proteins will only achieve their final native state once translation is completed. Nevertheless, it has been observed that proteins can be ubiquitinated during synthesis. The extent and the relevance of co-translational protein degradation, as well as the underlying molecular mechanisms, remain areas of open investigation. Recent studies made seminal advances in elucidating ribosome-associated quality control processes, and how their loss of function can lead to proteostasis failure and disease. Here, we discuss current understanding of the situations leading to the marking of nascent proteins for degradation before synthesis is completed, and the emerging quality controls pathways engaged in this task in eukaryotic cells. We also highlight the methods used to study co-translational quality control.
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Ng, Kah Ying, Guleycan Lutfullahoglu Bal, Uwe Richter, Omid Safronov, Lars Paulin, Cory D. Dunn, Ville O. Paavilainen, et al. "Nonstop mRNAs generate a ground state of mitochondrial gene expression noise." Science Advances 8, no. 46 (November 16, 2022). http://dx.doi.org/10.1126/sciadv.abq5234.
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A stop codon within the mRNA facilitates coordinated termination of protein synthesis, releasing the nascent polypeptide from the ribosome. This essential step in gene expression is impeded with transcripts lacking a stop codon, generating nonstop ribosome complexes. Here, we use deep sequencing to investigate sources of nonstop mRNAs generated from the human mitochondrial genome. We identify diverse types of nonstop mRNAs on mitochondrial ribosomes that are resistant to translation termination by canonical release factors. Failure to resolve these aberrations by the mitochondrial release factor in rescue (MTRFR) imparts a negative regulatory effect on protein synthesis that is associated with human disease. Our findings reveal a source of underlying noise in mitochondrial gene expression and the importance of responsive ribosome quality control mechanisms for cell fitness and human health.
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Müller, Claudia, Caillan Crowe-McAuliffe, and Daniel N. Wilson. "Ribosome Rescue Pathways in Bacteria." Frontiers in Microbiology 12 (March 18, 2021). http://dx.doi.org/10.3389/fmicb.2021.652980.
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Ribosomes that become stalled on truncated or damaged mRNAs during protein synthesis must be rescued for the cell to survive. Bacteria have evolved a diverse array of rescue pathways to remove the stalled ribosomes from the aberrant mRNA and return them to the free pool of actively translating ribosomes. In addition, some of these pathways target the damaged mRNA and the incomplete nascent polypeptide chain for degradation. This review highlights the recent developments in our mechanistic understanding of bacterial ribosomal rescue systems, including drop-off, trans-translation mediated by transfer-messenger RNA and small protein B, ribosome rescue by the alternative rescue factors ArfA and ArfB, as well as Bacillus ribosome rescue factor A, an additional rescue system found in some Gram-positive bacteria, such as Bacillus subtilis. Finally, we discuss the recent findings of ribosome-associated quality control in particular bacterial lineages mediated by RqcH and RqcP. The importance of rescue pathways for bacterial survival suggests they may represent novel targets for the development of new antimicrobial agents against multi-drug resistant pathogenic bacteria.