scholarly journals Antagonistic control of myofiber size and muscle protein quality control by the ubiquitin ligase UBR4 during aging

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Liam C. Hunt ◽  
Bronwen Schadeberg ◽  
Jared Stover ◽  
Benard Haugen ◽  
Vishwajeeth Pagala ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Quality Control ◽  
Ubiquitin Ligase ◽  
Muscle Function ◽  
Protein Quality ◽  
Contractile Function ◽  
Muscle Protein ◽  
Functional Decline ◽  
Protein Quality Control ◽  
Antagonistic Control

AbstractSarcopenia is a degenerative condition that consists in age-induced atrophy and functional decline of skeletal muscle cells (myofibers). A common hypothesis is that inducing myofiber hypertrophy should also reinstate myofiber contractile function but such model has not been extensively tested. Here, we find that the levels of the ubiquitin ligase UBR4 increase in skeletal muscle with aging, and that UBR4 increases the proteolytic activity of the proteasome. Importantly, muscle-specific UBR4 loss rescues age-associated myofiber atrophy in mice. However, UBR4 loss reduces the muscle specific force and accelerates the decline in muscle protein quality that occurs with aging in mice. Similarly, hypertrophic signaling induced via muscle-specific loss of UBR4/poe and of ESCRT members (HGS/Hrs, STAM, USP8) that degrade ubiquitinated membrane proteins compromises muscle function and shortens lifespan in Drosophila by reducing protein quality control. Altogether, these findings indicate that these ubiquitin ligases antithetically regulate myofiber size and muscle protein quality control.

scholarly journals Recent advances in measuring and understanding the regulation of exercise-mediated protein degradation in skeletal muscle

2021 ◽  
Author(s):  
Yusuke Nishimura ◽  
Ibrahim Musa ◽  
Lars Holm ◽  
Yu-Chiang Lai
Keyword(s):  
Skeletal Muscle ◽  
Quality Control ◽  
Protein Degradation ◽  
Protein Turnover ◽  
Degradation Rate ◽  
Protein Quality ◽  
Muscle Protein ◽  
Protein Quality Control ◽  
Muscle Protein Degradation ◽  
Protein Degradation Rate

Skeletal muscle protein turnover plays a crucial role in controlling muscle mass and protein quality control, including sarcomeric (structural and contractile) proteins. Protein turnover is a dynamic and continual process of protein synthesis and degradation. The ubiquitin proteasome system (UPS) is a key degradative system for protein degradation and protein quality control in skeletal muscle. UPS-mediated protein quality control is known to be impaired in ageing and diseases. Exercise is a well-recognized non-pharmacological approach to promote muscle protein turnover rates. Over the past decades, we have acquired substantial knowledge of molecular mechanisms of muscle protein synthesis after exercise. However, there has been considerable gaps in the mechanisms of how muscle protein degradation is regulated at the molecular level. The main challenge to understand muscle protein degradation is due in part to the lack of solid stable isotope tracer methodology to measure muscle protein degradation rate. Understanding the mechanisms of UPS with the concomitant measurement of protein degradation rate in skeletal muscle will help identify novel therapeutic strategies to ameliorate impaired protein turnover and protein quality control in ageing and diseases. Thus, the goal of this present review is to highlight how recent advances in the field may help improve our understanding of exercise-mediated protein degradation. We discuss 1) the emerging roles of protein phosphorylation and ubiquitylation modifications in regulating proteasome-mediated protein degradation after exercise and 2) methodological advances to measure in vivo myofibrillar protein degradation rate using stable isotope tracer methods.

scholarly journals Age-associated declines in mitochondrial biogenesis and protein quality control factors are minimized by exercise training

2012 ◽  
Vol 303 (2) ◽  
pp. R127-R134 ◽  
Author(s):  
Erika Koltai ◽  
Nikolett Hart ◽  
Albert W. Taylor ◽  
Sataro Goto ◽  
Jenny K. Ngo ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Quality Control ◽  
Exercise Training ◽  
Mitochondrial Biogenesis ◽  
Protein Quality ◽  
Mitochondrial Protein ◽  
Protein Quality Control ◽  
Treadmill Running ◽  
Common Finding ◽  
Moderate Intensity

A decline in mitochondrial biogenesis and mitochondrial protein quality control in skeletal muscle is a common finding in aging, but exercise training has been suggested as a possible cure. In this report, we tested the hypothesis that moderate-intensity exercise training could prevent the age-associated deterioration in mitochondrial biogenesis in the gastrocnemius muscle of Wistar rats. Exercise training, consisting of treadmill running at 60% of the initial V̇o2max, reversed or attenuated significant age-associated (detrimental) declines in mitochondrial mass (succinate dehydrogenase, citrate synthase, cytochrome- c oxidase-4, mtDNA), SIRT1 activity, AMPK, pAMPK, and peroxisome proliferator-activated receptor gamma coactivator 1-α, UCP3, and the Lon protease. Exercise training also decreased the gap between young and old animals in other measured parameters, including nuclear respiratory factor 1, mitochondrial transcription factor A, fission-1, mitofusin-1, and polynucleotide phosphorylase levels. We conclude that exercise training can help minimize detrimental skeletal muscle aging deficits by improving mitochondrial protein quality control and biogenesis.

scholarly journals Coupled protein quality control during nonsense mediated mRNA decay

2021 ◽  
Author(s):  
Alison J Inglis ◽  
Alina Guna ◽  
Angel Galvez Merchan ◽  
Akshaye Pal ◽  
Theodore K Esantsi ◽  
...  
Keyword(s):  
Quality Control ◽  
Protein Degradation ◽  
Ubiquitin Ligase ◽  
Mammalian Cells ◽  
Molecular Mechanisms ◽  
Protein Quality ◽  
Protein Quality Control ◽  
Mrna Degradation ◽  
Protein Product ◽  
Reporter System

Translation of mRNAs containing premature termination codons (PTCs) can result in truncated protein products with deleterious effects. Nonsense-mediated decay (NMD) is a surveillance path-way responsible for detecting and degrading PTC containing transcripts. While the molecular mechanisms governing mRNA degradation have been extensively studied, the fate of the nascent protein product remains largely uncharacterized. Here, we use a fluorescent reporter system in mammalian cells to reveal a selective degradation pathway specifically targeting the protein product of an NMD mRNA. We show that this process is post-translational, and dependent on an intact ubiquitin proteasome system. To systematically uncover factors involved in NMD-linked protein quality control, we conducted genome-wide flow cytometry-based screens. Our screens recovered known NMD factors, and suggested a lack of dependence on the canonical ribosome-quality control (RQC) pathway. Finally, one of the strongest hits in our screens was the E3 ubiquitin ligase CNOT4, a member of the CCR4-NOT complex, which is involved in initiating mRNA degradation. We show that CNOT4 is involved in NMD coupled protein degradation, and its role depends on a functional RING ubiquitin ligase domain. Our results demonstrate the existence of a targeted pathway for nascent protein degradation from PTC containing mRNAs, and provide a framework for identifying and characterizing factors involved in this process.

scholarly journals Loss of protein quality control gene UBR1 sensitizes Saccharomyces cerevisiae to the aminoglycoside hygromycin B

Fine Focus ◽  
2020 ◽  
Vol 6 (1) ◽  
pp. 76-83
Author(s):  
Avery M. Runnebohm ◽  
Melissa D. Evans ◽  
Adam E. Richardson ◽  
Samantha M. Turk ◽  
James B. Olesen ◽  
...  
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Quality Control ◽  
Ubiquitin Ligase ◽  
Protein Quality ◽  
Protein Quality Control ◽  
Eukaryotic Cells ◽  
Hygromycin B ◽  
Eukaryotic Microorganism ◽  
Human Enzyme ◽  
A Site

Ubr1 is a conserved ubiquitin ligase involved in the degradation of aberrant proteins in eukaryotic cells. The human enzyme is found mutated in patients with Johanson-Blizzard syndrome. We hypothesized that Ubr1 is necessary for optimal cellular fitness in conditions associated with elevated abundance of aberrant and misfolded proteins. Indeed, we found that loss of Ubr1 in the model eukaryotic microorganism Saccharomyces cerevisiae strongly sensitizes cells to hygromycin B, which reduces translational fidelity by causing ribosome A site distortion. Our results are consistent with a prominent role for Ubr1 in protein quality control. We speculate that disease manifestations in patients with Johanson-Blizzard syndrome are linked, at least in part, to defects in protein quality control caused by loss of Ubr1 function.

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 Aerobic exercise training rescues protein quality control disruption on white skeletal muscle induced by chronic kidney disease in rats

2017 ◽  
Vol 22 (3) ◽  
pp. 1452-1463 ◽  
Author(s):  
Wilson Max Almeida Monteiro De Moraes ◽  
Pamella Ramona Moraes de Souza ◽  
Nathalie Alves da Paixão ◽  
Luís Gustavo Oliveira de Sousa ◽  
Daniel Araki Ribeiro ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Chronic Kidney Disease ◽  
Quality Control ◽  
Kidney Disease ◽  
Exercise Training ◽  
Aerobic Exercise ◽  
Protein Quality ◽  
Protein Quality Control ◽  
Aerobic Exercise Training

scholarly journals The San1 Ubiquitin Ligase Functions Preferentially with Ubiquitin-conjugating Enzyme Ubc1 during Protein Quality Control

2016 ◽  
Vol 291 (36) ◽  
pp. 18778-18790 ◽  
Author(s):  
Rebeca Ibarra ◽  
Daniella Sandoval ◽  
Eric K. Fredrickson ◽  
Richard G. Gardner ◽  
Gary Kleiger
Keyword(s):  
Quality Control ◽  
Ubiquitin Ligase ◽  
Protein Quality ◽  
Protein Quality Control ◽  
Ubiquitin Conjugating Enzyme ◽  
Conjugating Enzyme

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.

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