Protein quality control at the ribosome: focus on RAC, NAC and RQC

2016 ◽  
Vol 60 (2) ◽  
pp. 203-212 ◽  
Author(s):  
Martin Gamerdinger
Keyword(s):  
Quality Control ◽  
Protein Production ◽  
Protein Quality ◽  
Nascent Polypeptide ◽  
Life And Death ◽  
Ribosomal Tunnel ◽  
Protein Biogenesis ◽  
Nascent Chain ◽  
Cellular Compartments ◽  
Polypeptide Chains

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.

scholarly journals The Crystal Structure of Archaeal Nascent Polypeptide-associated Complex (NAC) Reveals a Unique Fold and the Presence of a Ubiquitin-associated Domain

2005 ◽  
Vol 280 (16) ◽  
pp. 15849-15854 ◽  
Author(s):  
Thomas Spreter ◽  
Markus Pech ◽  
Birgitta Beatrix
Keyword(s):  
Crystal Structure ◽  
Protein Quality ◽  
Structural Features ◽  
Cellular Protein ◽  
Nascent Polypeptide ◽  
Nascent Chain ◽  
Ubiquitination Pathway ◽  
Protein Quality Control System ◽  
Cytosolic Factor ◽  
Cytosolic Factors

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.

scholarly journals Clearing Traffic Jams During Protein Translocation Across Membranes

2021 ◽  
Vol 8 ◽  
Author(s):  
Lihui Wang ◽  
Yihong Ye
Keyword(s):  
Quality Control ◽  
Endoplasmic Reticulum ◽  
Protein Folding ◽  
Lipid Bilayers ◽  
Protein Quality ◽  
Protein Translocation ◽  
Control Strategies ◽  
Protein Quality Control ◽  
Traffic Jams ◽  
Protein Biogenesis

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.

scholarly journals Protein quality control in the secretory pathway

2019 ◽  
Vol 218 (10) ◽  
pp. 3171-3187 ◽  
Author(s):  
Zhihao Sun ◽  
Jeffrey L. Brodsky
Keyword(s):  
Quality Control ◽  
Protein Folding ◽  
Secretory Pathway ◽  
Protein Quality ◽  
Protein Quality Control ◽  
Misfolded Proteins ◽  
Unfolded Protein ◽  
Protein Biogenesis ◽  
The Unfolded Protein Response ◽  
Protein Response

Protein folding is inherently error prone, especially in the endoplasmic reticulum (ER). Even with an elaborate network of molecular chaperones and protein folding facilitators, misfolding can occur quite frequently. To maintain protein homeostasis, eukaryotes have evolved a series of protein quality-control checkpoints. When secretory pathway quality-control pathways fail, stress response pathways, such as the unfolded protein response (UPR), are induced. In addition, the ER, which is the initial hub of protein biogenesis in the secretory pathway, triages misfolded proteins by delivering substrates to the proteasome or to the lysosome/vacuole through ER-associated degradation (ERAD) or ER-phagy. Some misfolded proteins escape the ER and are instead selected for Golgi quality control. These substrates are targeted for degradation after retrieval to the ER or delivery to the lysosome/vacuole. Here, we discuss how these guardian pathways function, how their activities intersect upon induction of the UPR, and how decisions are made to dispose of misfolded proteins in the secretory pathway.

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

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Ryo Yonashiro ◽  
Erich B Tahara ◽  
Mario H Bengtson ◽  
Maria Khokhrina ◽  
Holger Lorenz ◽  
...  
Keyword(s):  
Quality Control ◽  
Protein Aggregation ◽  
Polypeptide Chain ◽  
E3 Ligase ◽  
Aggregation Mechanism ◽  
Nascent Polypeptide ◽  
Ribosome Stalling ◽  
Dependent Protein ◽  
Carboxy Terminal ◽  
Polypeptide Chains

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.

scholarly journals Ubiquitin Ligase Redundancy and Nuclear-Cytoplasmic Localization in Yeast Protein Quality Control

Biomolecules ◽  
2021 ◽  
Vol 11 (12) ◽  
pp. 1821
Author(s):  
Carolyn Allain Breckel ◽  
Mark Hochstrasser
Keyword(s):  
Quality Control ◽  
Ubiquitin Ligase ◽  
Protein Quality ◽  
Three Dimensional ◽  
Protein Quality Control ◽  
Ubiquitin Ligases ◽  
Ubiquitin Proteasome System ◽  
Current Evidence ◽  
Cellular Processes ◽  
Cellular Compartments

The diverse functions of proteins depend on their proper three-dimensional folding and assembly. Misfolded cellular proteins can potentially harm cells by forming aggregates in their resident compartments that can interfere with vital cellular processes or sequester important factors. Protein quality control (PQC) pathways are responsible for the repair or destruction of these abnormal proteins. Most commonly, the ubiquitin-proteasome system (UPS) is employed to recognize and degrade those proteins that cannot be refolded by molecular chaperones. Misfolded substrates are ubiquitylated by a subset of ubiquitin ligases (also called E3s) that operate in different cellular compartments. Recent research in Saccharomyces cerevisiae has shown that the most prominent ligases mediating cytoplasmic and nuclear PQC have overlapping yet distinct substrate specificities. Many substrates have been characterized that can be targeted by more than one ubiquitin ligase depending on their localization, and cytoplasmic PQC substrates can be directed to the nucleus for ubiquitylation and degradation. Here, we review some of the major yeast PQC ubiquitin ligases operating in the nucleus and cytoplasm, as well as current evidence indicating how these ligases can often function redundantly toward substrates in these compartments.

Nascent polypeptide chains within the ribosomal tunnel analyzed by cryo-EM

Ribosomes ◽  
2011 ◽  
pp. 393-404
Author(s):  
Daniel N. Wilson ◽  
Shashi Bhushan ◽  
Thomas Becker ◽  
Roland Beckmann
Keyword(s):  
Nascent Polypeptide ◽  
Ribosomal Tunnel ◽  
Polypeptide Chains

scholarly journals Cooperativity between the Ribosome-Associated Chaperone Ssb/RAC and the Ubiquitin Ligase Ltn1 in Ubiquitination of Nascent Polypeptides

2020 ◽  
Vol 21 (18) ◽  
pp. 6815
Author(s):  
Arnab Ghosh ◽  
Natalia Shcherbik
Keyword(s):  
Quality Control ◽  
Ubiquitin Ligase ◽  
Protein Quality ◽  
Eukaryotic Cells ◽  
Surveillance Systems ◽  
Ribosomal Subunits ◽  
Proteotoxic Stress ◽  
Nascent Chain ◽  
Quantitative Western Blot

Eukaryotic cells have evolved multiple mechanisms to detect and eliminate aberrant polypeptides. Co-translational protein surveillance systems play an important role in these mechanisms. These systems include ribosome-associated protein quality control (RQC) that detects aberrant nascent chains stalled on ribosomes and promotes their ubiquitination and degradation by the proteasome, and ribosome-associated chaperone Ssb/RAC, which ensures correct nascent chain folding. Despite the known function of RQC and Ssb/ribosome-associated complex (RAC) in monitoring the quality of newly generated polypeptides, whether they cooperate during initial stages of protein synthesis remains unexplored. Here, we provide evidence that Ssb/RAC and the ubiquitin ligase Ltn1, the major component of RQC, display genetic and functional cooperativity. Overexpression of Ltn1 rescues growth suppression of the yeast strain-bearing deletions of SSB genes during proteotoxic stress. Moreover, Ssb/RAC promotes Ltn1-dependent ubiquitination of nascent chains associated with 80S ribosomal particles but not with translating ribosomes. Consistent with this finding, quantitative western blot analysis revealed lower levels of Ltn1 associated with 80S ribosomes and with free 60S ribosomal subunits in the absence of Ssb/RAC. We propose a mechanism in which Ssb/RAC facilitates recruitment of Ltn1 to ribosomes, likely by detecting aberrations in nascent chains and leading to their ubiquitination and degradation.

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