scholarly journals Heparan sulfate is a clearance receptor for aberrant extracellular proteins

2020 ◽  
Vol 219 (3) ◽  
Author(s):  
Eisuke Itakura ◽  
Momoka Chiba ◽  
Takeshi Murata ◽  
Akira Matsuura
Keyword(s):  
Quality Control ◽  
Heparan Sulfate ◽  
Mammalian Cells ◽  
Protein Quality ◽  
Amyloid Β ◽  
Degradation Pathway ◽  
Extracellular Proteins ◽  
Amyloid Β Peptide ◽  
Biochemical Analyses ◽  
Protein Quality Control System

The accumulation of aberrant proteins leads to various neurodegenerative disorders. Mammalian cells contain several intracellular protein degradation systems, including autophagy and proteasomal systems, that selectively remove aberrant intracellular proteins. Although mammals contain not only intracellular but also extracellular proteins, the mechanism underlying the quality control of aberrant extracellular proteins is poorly understood. Here, using a novel quantitative fluorescence assay and genome-wide CRISPR screening, we identified the receptor-mediated degradation pathway by which misfolded extracellular proteins are selectively captured by the extracellular chaperone Clusterin and undergo endocytosis via the cell surface heparan sulfate (HS) receptor. Biochemical analyses revealed that positively charged residues on Clusterin electrostatically interact with negatively charged HS. Furthermore, the Clusterin–HS pathway facilitates the degradation of amyloid β peptide and diverse leaked cytosolic proteins in extracellular space. Our results identify a novel protein quality control system for preserving extracellular proteostasis and highlight its role in preventing diseases associated with aberrant extracellular proteins.

scholarly journals Mapping the degradation pathway of a disease-linked aspartoacylase variant

PLoS Genetics ◽  
2021 ◽  
Vol 17 (4) ◽  
pp. e1009539
Author(s):  
Sarah K. Gersing ◽  
Yong Wang ◽  
Martin Grønbæk-Thygesen ◽  
Caroline Kampmeyer ◽  
Lene Clausen ◽  
...  
Keyword(s):  
Quality Control ◽  
Protein Quality ◽  
Protein Quality Control ◽  
Proteasomal Degradation ◽  
Degradation Pathway ◽  
Wild Type ◽  
Protein Variant ◽  
Stable Conformation ◽  
Spongy Degeneration ◽  
Brain White Matter

Canavan disease is a severe progressive neurodegenerative disorder that is characterized by swelling and spongy degeneration of brain white matter. The disease is genetically linked to polymorphisms in the aspartoacylase (ASPA) gene, including the substitution C152W. ASPA C152W is associated with greatly reduced protein levels in cells, yet biophysical experiments suggest a wild-type like thermal stability. Here, we use ASPA C152W as a model to investigate the degradation pathway of a disease-causing protein variant. When we expressed ASPA C152W in Saccharomyces cerevisiae, we found a decreased steady state compared to wild-type ASPA as a result of increased proteasomal degradation. However, molecular dynamics simulations of ASPA C152W did not substantially deviate from wild-type ASPA, indicating that the native state is structurally preserved. Instead, we suggest that the C152W substitution interferes with the de novo folding pathway resulting in increased proteasomal degradation before reaching its stable conformation. Systematic mapping of the protein quality control components acting on misfolded and aggregation-prone species of C152W, revealed that the degradation is highly dependent on the molecular chaperone Hsp70, its co-chaperone Hsp110 as well as several quality control E3 ubiquitin-protein ligases, including Ubr1. In addition, the disaggregase Hsp104 facilitated refolding of aggregated ASPA C152W, while Cdc48 mediated degradation of insoluble ASPA protein. In human cells, ASPA C152W displayed increased proteasomal turnover that was similarly dependent on Hsp70 and Hsp110. Our findings underscore the use of yeast to determine the protein quality control components involved in the degradation of human pathogenic variants in order to identify potential therapeutic targets.

scholarly journals A Crucial Role for the Protein Quality Control System in Motor Neuron Diseases

2020 ◽  
Vol 12 ◽  
Author(s):  
Riccardo Cristofani ◽  
Valeria Crippa ◽  
Maria Elena Cicardi ◽  
Barbara Tedesco ◽  
Veronica Ferrari ◽  
...  
Keyword(s):  
Quality Control ◽  
Control System ◽  
Motor Neuron ◽  
Crucial Role ◽  
Protein Quality ◽  
Protein Quality Control ◽  
Quality Control System ◽  
Motor Neuron Diseases ◽  
Protein Quality Control System

scholarly journals The Mitochondrial Lon Protease: Novel Functions off the Beaten Track?

Biomolecules ◽  
2020 ◽  
Vol 10 (2) ◽  
pp. 253 ◽  
Author(s):  
Wolfgang Voos ◽  
Karen Pollecker
Keyword(s):  
Mammalian Cells ◽  
Protein Quality ◽  
Proteolytic Enzymes ◽  
Mitochondrial Gene ◽  
Protective Action ◽  
Stress Conditions ◽  
Endogenous Protein ◽  
The Matrix ◽  
Beaten Track ◽  
Protein Quality Control System

To maintain organellar function, mitochondria contain an elaborate endogenous protein quality control system. As one of the two soluble energy-dependent proteolytic enzymes in the matrix compartment, the protease Lon is a major component of this system, responsible for the degradation of misfolded proteins, in particular under oxidative stress conditions. Lon defects have been shown to negatively affect energy production by oxidative phosphorylation but also mitochondrial gene expression. In this review, recent studies on the role of Lon in mammalian cells, in particular on its protective action under diverse stress conditions and its relationship to important human diseases are summarized and commented.

scholarly journals Roles and Mechanisms of the Protein Quality Control System in Alzheimer’s Disease

2021 ◽  
Vol 23 (1) ◽  
pp. 345
Author(s):  
Yaping Liu ◽  
Runrong Ding ◽  
Ze Xu ◽  
Yuan Xue ◽  
Dongdong Zhang ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Quality Control ◽  
Control System ◽  
Protein Quality ◽  
Early Stage ◽  
Senile Plaques ◽  
Protein Quality Control ◽  
Quality Control System ◽  
Protein Quality Control System

Alzheimer’s disease (AD) is characterized by the deposition of senile plaques (SPs) and the formation of neurofibrillary tangles (NTFs), as well as neuronal dysfunctions in the brain, but in fact, patients have shown a sustained disease progression for at least 10 to 15 years before these pathologic biomarkers can be detected. Consequently, as the most common chronic neurological disease in the elderly, the challenge of AD treatment is that it is short of effective biomarkers for early diagnosis. The protein quality control system is a collection of cellular pathways that can recognize damaged proteins and thereby modulate their turnover. Abundant evidence indicates that the accumulation of abnormal proteins in AD is closely related to the dysfunction of the protein quality control system. In particular, it is the synthesis, degradation, and removal of essential biological components that have already changed in the early stage of AD, which further encourages us to pay more attention to the protein quality control system. The review mainly focuses on the endoplasmic reticulum system (ERS), autophagy–lysosome system (ALS) and the ubiquitin–proteasome system (UPS), and deeply discusses the relationship between the protein quality control system and the abnormal proteins of AD, which can not only help us to understand how and why the complex regulatory system becomes malfunctional during AD progression, but also provide more novel therapeutic strategies to prevent the development of AD.

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