Faculty Opinions recommendation of Characterization of rapidly degraded polypeptides in mammalian cells reveals a novel layer of nascent protein quality control.

2005 ◽  
Author(s):  
Peter Van Endert
Keyword(s):  
Quality Control ◽  
Mammalian Cells ◽  
Protein Quality ◽  
Protein Quality Control

scholarly journals Characterization of Rapidly Degraded Polypeptides in Mammalian Cells Reveals a Novel Layer of Nascent Protein Quality Control

2005 ◽  
Vol 281 (1) ◽  
pp. 392-400 ◽  
Author(s):  
Shu-Bing Qian ◽  
Michael F. Princiotta ◽  
Jack R. Bennink ◽  
Jonathan W. Yewdell
Keyword(s):  
Quality Control ◽  
Mammalian Cells ◽  
Protein Quality ◽  
Protein Quality Control

scholarly journals The Toxicity of a Novel Antifungal Compound Is Modulated by Endoplasmic Reticulum-Associated Protein Degradation Components

2015 ◽  
Vol 60 (3) ◽  
pp. 1438-1449 ◽  
Author(s):  
Shriya Raj ◽  
Karthik Krishnan ◽  
David S. Askew ◽  
Olivier Helynck ◽  
Peggy Suzanne ◽  
...  
Keyword(s):  
Quality Control ◽  
Endoplasmic Reticulum ◽  
Protein Degradation ◽  
Mammalian Cells ◽  
Protein Quality ◽  
Protein Quality Control ◽  
Antifungal Compound ◽  
Content Type ◽  
Enhanced Sensitivity ◽  
Fungal Organisms

In a search for new antifungal compounds, we screened a library of 4,454 chemicals for toxicity against the human fungal pathogenAspergillus fumigatus. We identified sr7575, a molecule that inhibits growth of the evolutionary distant fungiA. fumigatus,Cryptococcus neoformans,Candida albicans, andSaccharomyces cerevisiaebut lacks acute toxicity for mammalian cells. To gain insight into the mode of inhibition, sr7575 was screened against 4,885S. cerevisiaemutants from the systematic collection of haploid deletion strains and 977 barcoded haploid DAmP (decreased abundance by mRNA perturbation) strains in which the function of essential genes was perturbed by the introduction of a drug resistance cassette downstream of the coding sequence region. Comparisons with previously published chemogenomic screens revealed that the set of mutants conferring sensitivity to sr7575 was strikingly narrow, affecting components of the endoplasmic reticulum-associated protein degradation (ERAD) stress response and the ER membrane protein complex (EMC). ERAD-deficient mutants were hypersensitive to sr7575 in bothS. cerevisiaeandA. fumigatus, indicating a conserved mechanism of growth inhibition between yeast and filamentous fungi. Although the unfolded protein response (UPR) is linked to ERAD regulation, sr7575 did not trigger the UPR inA. fumigatusand UPR mutants showed no enhanced sensitivity to the compound. The data from this chemogenomic analysis demonstrate that sr7575 exerts its antifungal activity by disrupting ER protein quality control in a manner that requires ERAD intervention but bypasses the need for the canonical UPR. ER protein quality control is thus a specific vulnerability of fungal organisms that might be exploited for antifungal drug development.

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 Biochemical Characterization of Protein Quality Control Mechanisms during Disease Progression in the C22 Mouse Model of CMT1A

ASN NEURO ◽  
2013 ◽  
Vol 5 (5) ◽  
pp. AN20130024 ◽  
Author(s):  
Vinita G. Chittoor ◽  
Lee Sooyeon ◽  
Sunitha Rangaraju ◽  
Jessica R. Nicks ◽  
Jordan T. Schmidt ◽  
...  
Keyword(s):  
Quality Control ◽  
Mouse Model ◽  
Disease Progression ◽  
Protein Quality ◽  
Biochemical Characterization ◽  
Protein Quality Control ◽  
Control Mechanisms

scholarly journals USP7 regulates ALS-associated proteotoxicity and quality control through the NEDD4L–SMAD pathway

2020 ◽  
Vol 117 (45) ◽  
pp. 28114-28125
Author(s):  
Tao Zhang ◽  
Goran Periz ◽  
Yu-Ning Lu ◽  
Jiou Wang
Keyword(s):  
Quality Control ◽  
Neurodegenerative Diseases ◽  
Protein Misfolding ◽  
Mammalian Cells ◽  
Transforming Growth Factor ◽  
Protein Quality ◽  
Protein Quality Control ◽  
Transforming Growth Factor Β ◽  
Misfolded Proteins ◽  
A Genome

An imbalance in cellular homeostasis occurring as a result of protein misfolding and aggregation contributes to the pathogeneses of neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). Here, we report the identification of a ubiquitin-specific protease, USP7, as a regulatory switch in a protein quality-control system that defends against proteotoxicity. A genome-wide screen in aCaenorhabditis elegansmodel of SOD1-linked ALS identified the USP7 ortholog as a suppressor of proteotoxicity in the nervous system. The actions of USP7 orthologs on misfolded proteins were found to be conserved inDrosophilaand mammalian cells. USP7 acts on protein quality control through the SMAD2 transcription modulator of the transforming growth factor β pathway, which activates autophagy and enhances the clearance of misfolded proteins. USP7 deubiquitinates the E3 ubiquitin ligase NEDD4L, which mediates the degradation of SMAD2. Inhibition of USP7 protected against proteotoxicity in mammalian neurons, and SMAD2 was found to be dysregulated in the nervous systems of ALS patients. These findings reveal a regulatory pathway of protein quality control that is implicated in the proteotoxicity-associated neurodegenerative diseases.

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