scholarly journals The ribosome-bound quality control complex remains associated to aberrant peptides during their proteasomal targeting and interacts with Tom1 to limit protein aggregation

2017 ◽  
Vol 28 (9) ◽  
pp. 1165-1176 ◽  
Author(s):  
Quentin Defenouillère ◽  
Abdelkader Namane ◽  
John Mouaikel ◽  
Alain Jacquier ◽  
Micheline Fromont-Racine
Keyword(s):  
Quality Control ◽  
Protein Aggregation ◽  
Ubiquitin Ligase ◽  
Protein Quality ◽  
Translation Termination ◽  
E3 Ubiquitin Ligase ◽  
Protein Quality Control ◽  
Control Mechanisms ◽  
Ubiquitin Ligase Activity ◽  
Control Complex

Protein quality control mechanisms eliminate defective polypeptides to ensure proteostasis and to avoid the toxicity of protein aggregates. In eukaryotes, the ribosome-bound quality control (RQC) complex detects aberrant nascent peptides that remain stalled in 60S ribosomal particles due to a dysfunction in translation termination. The RQC complex polyubiquitylates aberrant polypeptides and recruits a Cdc48 hexamer to extract them from 60S particles in order to escort them to the proteasome for degradation. Whereas the steps from stalled 60S recognition to aberrant peptide polyubiquitylation by the RQC complex have been described, the mechanism leading to proteasomal degradation of these defective translation products remains unknown. We show here that the RQC complex also exists as a ribosome-unbound complex during the escort of aberrant peptides to the proteasome. In addition, we identify a new partner of this light version of the RQC complex, the E3 ubiquitin ligase Tom1. Tom1 interacts with aberrant nascent peptides and is essential to limit their accumulation and aggregation in the absence of Rqc1; however, its E3 ubiquitin ligase activity is not required. Taken together, these results reveal new roles for Tom1 in protein quality control, aggregate prevention, and, therefore, proteostasis maintenance.

scholarly journals CRL2 aids elimination of truncated selenoproteins produced by failed UGA/Sec decoding

Science ◽  
2015 ◽  
Vol 349 (6243) ◽  
pp. 91-95 ◽  
Author(s):  
Hsiu-Chuan Lin ◽  
Szu-Chi Ho ◽  
Yi-Yun Chen ◽  
Kay-Hooi Khoo ◽  
Pang-Hung Hsu ◽  
...  
Keyword(s):  
Quality Control ◽  
Control System ◽  
Protein Degradation ◽  
Genetic Code ◽  
Ubiquitin Ligase ◽  
Protein Quality ◽  
Translation Termination ◽  
Protein Quality Control ◽  
Selenium Intake ◽  
Protein Quality Control System

Selenocysteine (Sec) is translated from the codon UGA, typically a termination signal. Codon duality extends the genetic code; however, the coexistence of two competing UGA-decoding mechanisms immediately compromises proteome fidelity. Selenium availability tunes the reassignment of UGA to Sec. We report a CRL2 ubiquitin ligase–mediated protein quality-control system that specifically eliminates truncated proteins that result from reassignment failures. Exposing the peptide immediately N-terminal to Sec, a CRL2 recognition degron, promotes protein degradation. Sec incorporation destroys the degron, protecting read-through proteins from detection by CRL2. Our findings reveal a coupling between directed translation termination and proteolysis-assisted protein quality control, as well as a cellular strategy to cope with fluctuations in organismal selenium intake.

scholarly journals Inverse Correlation Between MPSR1 E3 Ubiquitin Ligase and HSP90.1 Balances Cytoplasmic Protein Quality Control

2019 ◽  
Vol 180 (2) ◽  
pp. 1230-1240 ◽  
Author(s):  
Jong Hum Kim ◽  
Tae Rin Oh ◽  
Seok Keun Cho ◽  
Seong Wook Yang ◽  
Woo Taek Kim
Keyword(s):  
Quality Control ◽  
Ubiquitin Ligase ◽  
Protein Quality ◽  
E3 Ubiquitin Ligase ◽  
Protein Quality Control ◽  
Inverse Correlation ◽  
Cytoplasmic Protein

scholarly journals Role of a ribosome-associated E3 ubiquitin ligase in protein quality control

Nature ◽  
2010 ◽  
Vol 467 (7314) ◽  
pp. 470-473 ◽  
Author(s):  
Mario H. Bengtson ◽  
Claudio A. P. Joazeiro
Keyword(s):  
Quality Control ◽  
Ubiquitin Ligase ◽  
Protein Quality ◽  
E3 Ubiquitin Ligase ◽  
Protein Quality Control

Cytosolic protein quality control machinery: Interactions of Hsp70 with a network of co-chaperones and substrates

2021 ◽  
pp. 153537022199981
Author(s):  
Chamithi Karunanayake ◽  
Richard C Page
Keyword(s):  
Quality Control ◽  
Protein Quality ◽  
Protein Quality Control ◽  
Structural Features ◽  
Cellular Protein ◽  
Mechanisms Of Action ◽  
Control Mechanisms ◽  
Nucleotide Exchange ◽  
Domain Organization ◽  
Nucleotide Exchange Factors

The chaperone heat shock protein 70 (Hsp70) and its network of co-chaperones serve as a central hub of cellular protein quality control mechanisms. Domain organization in Hsp70 dictates ATPase activity, ATP dependent allosteric regulation, client/substrate binding and release, and interactions with co-chaperones. The protein quality control activities of Hsp70 are classified as foldase, holdase, and disaggregase activities. Co-chaperones directly assisting protein refolding included J domain proteins and nucleotide exchange factors. However, co-chaperones can also be grouped and explored based on which domain of Hsp70 they interact. Here we discuss how the network of cytosolic co-chaperones for Hsp70 contributes to the functions of Hsp70 while closely looking at their structural features. Comparison of domain organization and the structures of co-chaperones enables greater understanding of the interactions, mechanisms of action, and roles played in protein quality control.

scholarly journals Targeting Protein Quality Control Mechanisms by Natural Products to Promote Healthy Ageing

Molecules ◽  
2018 ◽  
Vol 23 (5) ◽  
pp. 1219 ◽  
Author(s):  
Sophia Wedel ◽  
Maria Manola ◽  
Maria Cavinato ◽  
Ioannis Trougakos ◽  
Pidder Jansen-Dürr
Keyword(s):  
Quality Control ◽  
Natural Products ◽  
Protein Quality ◽  
Protein Quality Control ◽  
Healthy Ageing ◽  
Control Mechanisms

scholarly journals Phosphorylation Modifications Regulating Cardiac Protein Quality Control Mechanisms

2020 ◽  
Vol 11 ◽  
Author(s):  
Sumita Mishra ◽  
Brittany L. Dunkerly-Eyring ◽  
Gizem Keceli ◽  
Mark J. Ranek
Keyword(s):  
Quality Control ◽  
Protein Quality ◽  
Protein Quality Control ◽  
Control Mechanisms

Protein quality control at the mitochondrion

2016 ◽  
Vol 60 (2) ◽  
pp. 213-225 ◽  
Author(s):  
Wolfgang Voos ◽  
Witold Jaworek ◽  
Anne Wilkening ◽  
Michael Bruderek
Keyword(s):  
Quality Control ◽  
Structural Integrity ◽  
Protein Quality ◽  
Mitochondrial Protein ◽  
Protein Quality Control ◽  
Eukaryotic Cell ◽  
Control Mechanisms ◽  
Biochemical Processes ◽  
Unfolded Protein ◽  
Protein Response

Mitochondria are essential constituents of a eukaryotic cell by supplying ATP and contributing to many mayor metabolic processes. As endosymbiotic organelles, they represent a cellular subcompartment exhibiting many autonomous functions, most importantly containing a complete endogenous machinery responsible for protein expression, folding and degradation. This article summarizes the biochemical processes and the enzymatic components that are responsible for maintaining mitochondrial protein homoeostasis. As mitochondria lack a large part of the required genetic information, most proteins are synthesized in the cytosol and imported into the organelle. After reaching their destination, polypeptides must fold and assemble into active proteins. Under pathological conditions, mitochondrial proteins become misfolded or damaged and need to be repaired with the help of molecular chaperones or eventually removed by specific proteases. Failure of these protein quality control mechanisms results in loss of mitochondrial function and structural integrity. Recently, novel mechanisms have been identified that support mitochondrial quality on the organellar level. A mitochondrial unfolded protein response allows the adaptation of chaperone and protease activities. Terminally damaged mitochondria may be removed by a variation of autophagy, termed mitophagy. An understanding of the role of protein quality control in mitochondria is highly relevant for many human pathologies, in particular neurodegenerative diseases.

scholarly journals The Cochaperone HspBP1 Inhibits the CHIP Ubiquitin Ligase and Stimulates the Maturation of the Cystic Fibrosis Transmembrane Conductance Regulator

2004 ◽  
Vol 15 (9) ◽  
pp. 4003-4010 ◽  
Author(s):  
Simon Alberti ◽  
Karsten Böhse ◽  
Verena Arndt ◽  
Anton Schmitz ◽  
Jörg Höhfeld
Keyword(s):  
Cystic Fibrosis ◽  
Quality Control ◽  
Ubiquitin Ligase ◽  
Molecular Chaperones ◽  
Protein Quality ◽  
Regulatory Mechanism ◽  
Transmembrane Conductance Regulator ◽  
Transmembrane Conductance ◽  
Ubiquitin Ligase Activity ◽  
Cystic Fibrosis Transmembrane

The CHIP ubiquitin ligase turns molecular chaperones into protein degradation factors. CHIP associates with the chaperones Hsc70 and Hsp90 during the regulation of signaling pathways and during protein quality control, and directs chaperone-bound clients to the proteasome for degradation. Obviously, this destructive activity should be carefully controlled. Here, we identify the cochaperone HspBP1 as an inhibitor of CHIP. HspBP1 attenuates the ubiquitin ligase activity of CHIP when complexed with Hsc70. As a consequence, HspBP1 interferes with the CHIP-induced degradation of immature forms of the cystic fibrosis transmembrane conductance regulator (CFTR) and stimulates CFTR maturation. Our data reveal a novel regulatory mechanism that determines folding and degradation activities of molecular chaperones.

scholarly journals The nucleolus functions as a phase-separated protein quality control compartment

Science ◽  
2019 ◽  
Vol 365 (6451) ◽  
pp. 342-347 ◽  
Author(s):  
F. Frottin ◽  
F. Schueder ◽  
S. Tiwary ◽  
R. Gupta ◽  
R. Körner ◽  
...  
Keyword(s):  
Quality Control ◽  
Protein Quality ◽  
Protein Quality Control ◽  
Misfolded Proteins ◽  
Control Mechanisms ◽  
Culture Cells ◽  
Irreversible Aggregation ◽  
Nuclear Proteome ◽  
Prolonged Stress

The nuclear proteome is rich in stress-sensitive proteins, which suggests that effective protein quality control mechanisms are in place to ensure conformational maintenance. We investigated the role of the nucleolus in this process. In mammalian tissue culture cells under stress conditions, misfolded proteins entered the granular component (GC) phase of the nucleolus. Transient associations with nucleolar proteins such as NPM1 conferred low mobility to misfolded proteins within the liquid-like GC phase, avoiding irreversible aggregation. Refolding and extraction of proteins from the nucleolus during recovery from stress was Hsp70-dependent. The capacity of the nucleolus to store misfolded proteins was limited, and prolonged stress led to a transition of the nucleolar matrix from liquid-like to solid, with loss of reversibility and dysfunction in quality control. Thus, we suggest that the nucleolus has chaperone-like properties and can promote nuclear protein maintenance under stress.

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