Protein Quality Control: Part I—Molecular Chaperones and the Ubiquitin-Proteasome System

2015 ◽  
pp. 129-157
Author(s):  
Martin Beckerman
Keyword(s):  
Quality Control ◽  
Molecular Chaperones ◽  
Protein Quality ◽  
Protein Quality Control ◽  
Ubiquitin Proteasome System ◽  
Ubiquitin Proteasome ◽  
Control Part

scholarly journals The Degradation-promoting Roles of Deubiquitinases Ubp6 and Ubp3 in Cytosolic and ER Protein Quality Control

2020 ◽  
Author(s):  
Hongyi Wu ◽  
Davis T.W. Ng ◽  
Ian Cheong ◽  
Paul Matsudaira
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Quality Control ◽  
Molecular Chaperones ◽  
Protein Quality ◽  
Protein Quality Control ◽  
Ubiquitin Proteasome System ◽  
Misfolded Proteins ◽  
Intracellular Proteins ◽  
Ubiquitin Proteasome ◽  
Free Ubiquitin

AbstractThe quality control of intracellular proteins is achieved by degrading misfolded proteins which cannot be refolded by molecular chaperones. In eukaryotes, such degradation is handled primarily by the ubiquitin-proteasome system. However, it remains unclear whether and how protein quality control deploys various deubiquitinases. To address this question, we screened deletions or mutation of the 20 deubiquitinase genes in Saccharomyces cerevisiae and discovered that almost half of the mutations slowed the removal of misfolded proteins whereas none of the remaining mutations accelerated this process significantly. Further characterization revealed that Ubp6 maintains the level of free ubiquitin to promote the elimination of misfolded cytosolic proteins, while Ubp3 supports the degradation of misfolded cytosolic and ER luminal proteins by different mechanisms.

scholarly journals TTC3-Mediated Protein Quality Control, A Potential Mechanism for Cognitive Impairment

2021 ◽  
Author(s):  
Xu Zhou ◽  
Xiongjin Chen ◽  
Tingting Hong ◽  
Miaoping Zhang ◽  
Yujie Cai ◽  
...  
Keyword(s):  
Quality Control ◽  
Cognitive Impairment ◽  
Protein Quality ◽  
Protein Quality Control ◽  
Ubiquitin Proteasome System ◽  
Research Progress ◽  
Repeat Domain ◽  
Ubiquitin Proteasome ◽  
Domain 3

AbstractThe tetrapeptide repeat domain 3 (TTC3) gene falls within Down's syndrome (DS) critical region. Cognitive impairment is a common phenotype of DS and Alzheimer’s disease (AD), and overexpression of TTC3 can accelerate cognitive decline, but the specific mechanism is unknown. The TTC3-mediated protein quality control (PQC) mechanism, similar to the PQC system, is divided into three parts: it acts as a cochaperone to assist proteins in folding correctly; it acts as an E3 ubiquitin ligase (E3s) involved in protein degradation processes through the ubiquitin–proteasome system (UPS); and it may also eventually cause autophagy by affecting mitochondrial function. Thus, this article reviews the research progress on the structure, function, and metabolism of TTC3, including the recent research progress on TTC3 in DS and AD; the role of TTC3 in cognitive impairment through PQC in combination with the abovementioned attributes of TTC3; and the potential targets of TTC3 in the treatment of such diseases.

Protein Quality Control in Neurodegeneration and Neuroprotection

2020 ◽  
pp. 1-24
Author(s):  
Yasmeena Akhter ◽  
Jahangir Nabi ◽  
Hinna Hamid ◽  
Nahida Tabassum ◽  
Faheem Hyder Pottoo ◽  
...  
Keyword(s):  
Quality Control ◽  
Neurodegenerative Disorders ◽  
Protein Quality ◽  
Protein Quality Control ◽  
Ubiquitin Proteasome System ◽  
Security System ◽  
Conformational Disorders ◽  
Ubiquitin Proteasome ◽  
Multi Level

Proteostasis is essential for regulating the integrity of the proteome. Disruption of proteostasis under some rigorous conditions leads to the aggregation and accumulation of misfolded toxic proteins, which plays a central role in the pathogenesis of protein conformational disorders. The protein quality control (PQC) system serves as a multi-level security system to shield cells from abnormal proteins. The intrinsic PQC systems maintaining proteostasis include the ubiquitin-proteasome system (UPS), chaperon-mediated autophagy (CMA), and autophagy-lysosome pathway (ALP) that serve to target misfolded proteins for unfolding, refolding, or degradation. Alterations of PQC systems in neurons have been implicated in the pathogenesis of various neurodegenerative disorders. This chapter provides an overview of PQC pathways to set a framework for discussion of the role of PQC in neurodegenerative disorders. Additionally, various pharmacological approaches targeting PQC are summarized.

scholarly journals Disease-linked mutations trigger exposure of a protein quality control degron in the DHFR protein

2021 ◽  
Author(s):  
Caroline Kampmeyer ◽  
Sven Larsen-Ledet ◽  
Morten Rose Wagnkilde ◽  
Mathias Michelsen ◽  
Henriette K. M. Iversen ◽  
...  
Keyword(s):  
Quality Control ◽  
Protein Quality ◽  
Protein Quality Control ◽  
Ubiquitin Proteasome System ◽  
Yeast Cells ◽  
Cell Cycle Regulators ◽  
Missense Variants ◽  
Hydrogen Deuterium ◽  
Ubiquitin Proteasome ◽  
Protein Ligases

Degrons are short stretches of amino acids or structural motifs that are embedded in proteins. They mediate recognition by E3 ubiquitin-protein ligases and thus confer protein degradation via the ubiquitin-proteasome system. Well-described degrons include the N-degrons, destruction boxes, and the PIP degrons, which mediate the controlled degradation of various proteins including signaling components and cell cycle regulators. In comparison, the so-called protein quality control (PQC) degrons that mediate the degradation of structurally destabilized or misfolded proteins are not well described. Here, we show that disease-linked DHFR missense variants are structurally destabilized and chaperone-dependent proteasome targets. We systematically mapped regions within DHFR to assess those that act as cytosolic PQC degrons in yeast cells. Two regions, DHFR-Deg13-36 (here Deg1) and DHFR-Deg61-84 (here Deg2), act as degrons and conferred degradation to unrelated fusion partners. The proteasomal turnover of Deg2 was dependent on the molecular chaperone Hsp70. Structural analyses by NMR and hydrogen/deuterium exchange revealed that Deg2 is buried in wild-type DHFR, but becomes transiently exposed in the disease-linked missense variants.

scholarly journals Selective autophagic clearance of protein aggregates is mediated by the autophagy receptor, TAX1BP1

2019 ◽  
Author(s):  
Shireen A. Sarraf ◽  
Hetal V. Shah ◽  
Gil Kanfer ◽  
Michael E. Ward ◽  
Richard J. Youle
Keyword(s):  
Quality Control ◽  
Protein Quality ◽  
Protein Quality Control ◽  
Protein Aggregates ◽  
Ubiquitin Proteasome System ◽  
Cellular Homeostasis ◽  
Receptor Proteins ◽  
Proteotoxic Stress ◽  
Polyq Protein ◽  
Ubiquitin Proteasome

AbstractMisfolded protein aggregates can disrupt cellular homeostasis and cause toxicity, a hallmark of numerous neurodegenerative diseases. Protein quality control by the ubiquitin proteasome system (UPS) and autophagy is vital for clearance of aggregates and maintenance of cellular homeostasis1. Autophagy receptor proteins bridge the interaction between ubiquitinated proteins and the autophagy machinery allowing selective elimination of cargo2. Aggrephagy is critical to protein quality control, but how aggregates are recognized and targeted for degradation is not well understood. Here we examine the requirements for 5 autophagy receptor proteins: OPTN, NBR1, p62, NDP52, and TAX1BP1 in proteotoxic stress-induced aggregate clearance. Endogenous TAX1BP1 is both recruited to and required for the clearance of stress-induced aggregates while overexpression of TAX1BP1 increases aggregate clearance through autophagy. Furthermore, TAX1BP1 depletion sensitizes cells to proteotoxic stress and Huntington’s disease-linked polyQ proteins, whereas TAX1BP1 overexpression clears cells of polyQ protein aggregates by autophagy. We propose a broad role for TAX1BP1 in the clearance of cytotoxic proteins, thus identifying a new mode of clearance of protein inclusions.

Protein Quality Control of the Endoplasmic Reticulum and Ubiquitin–Proteasome-Triggered Degradation of Aberrant Proteins: Yeast Pioneers the Path

2018 ◽  
Vol 87 (1) ◽  
pp. 751-782 ◽  
Author(s):  
Nicole Berner ◽  
Karl-Richard Reutter ◽  
Dieter H. Wolf
Keyword(s):  
Quality Control ◽  
Endoplasmic Reticulum ◽  
Protein Quality ◽  
Protein Structures ◽  
Protein Quality Control ◽  
Ubiquitin Proteasome System ◽  
Misfolded Proteins ◽  
Secretory Proteins ◽  
Structural Alterations ◽  
Ubiquitin Proteasome

Cells must constantly monitor the integrity of their macromolecular constituents. Proteins are the most versatile class of macromolecules but are sensitive to structural alterations. Misfolded or otherwise aberrant protein structures lead to dysfunction and finally aggregation. Their presence is linked to aging and a plethora of severe human diseases. Thus, misfolded proteins have to be rapidly eliminated. Secretory proteins constitute more than one-third of the eukaryotic proteome. They are imported into the endoplasmic reticulum (ER), where they are folded and modified. A highly elaborated machinery controls their folding, recognizes aberrant folding states, and retrotranslocates permanently misfolded proteins from the ER back to the cytosol. In the cytosol, they are degraded by the highly selective ubiquitin–proteasome system. This process of protein quality control followed by proteasomal elimination of the misfolded protein is termed ER-associated degradation (ERAD), and it depends on an intricate interplay between the ER and the cytosol.

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