scholarly journals The Intertwining of Autophagy and the Ubiquitin Proteasome System in Podocyte (Patho)Physiology

2021 ◽  
Vol 55 (S4) ◽  
pp. 68-95
Keyword(s):  
Protein Aggregates ◽  
Ubiquitin Proteasome System ◽  
Regulatory Mechanisms ◽  
Disease Development ◽  
Protein Homeostasis ◽  
Differential Impact ◽  
Podocyte Injury ◽  
Ubiquitin Proteasome ◽  
Lysosomal System

Protein homeostasis strongly depends on the targeted and selective removal of unneeded or flawed proteins, of protein aggregates, and of damaged or excess organelles by the two main intracellular degradative systems, namely the ubiquitin proteasomal system (UPS) and the autophagosomal lysosomal system. Despite representing completely distinct mechanisms of degradation, which underlie differing regulatory mechanisms, growing evidence suggests that the UPS and autophagy strongly interact especially in situations of overwhelming and impairment, and that both are involved in podocyte proteostasis and in the pathogenesis of podocyte injury. The differential impact of autophagy and the UPS on podocyte biology and on podocyte disease development and progression is not understood. Recent advances in understanding the role of the UPS and autophagy in podocyte biology are reviewed here.

scholarly journals Functions and Therapeutic Potential of Extracellular Hsp60, Hsp70, and Hsp90 in Neuroinflammatory Disorders

2021 ◽  
Vol 11 (2) ◽  
pp. 736
Author(s):  
Giusi Alberti ◽  
Letizia Paladino ◽  
Alessandra Maria Vitale ◽  
Celeste Caruso Bavisotto ◽  
Everly Conway de Macario ◽  
...  
Keyword(s):  
Molecular Chaperones ◽  
Molecular Mechanisms ◽  
Therapeutic Potential ◽  
Ubiquitin Proteasome System ◽  
Protein Homeostasis ◽  
Canonical Function ◽  
Cytoprotective Activity ◽  
Ubiquitin Proteasome ◽  
Chaperone Mediated Autophagy

Neuroinflammation is implicated in central nervous system (CNS) diseases, but the molecular mechanisms involved are poorly understood. Progress may be accelerated by developing a comprehensive view of the pathogenesis of CNS disorders, including the immune and the chaperone systems (IS and CS). The latter consists of the molecular chaperones; cochaperones; and chaperone cofactors, interactors, and receptors of an organism and its main collaborators in maintaining protein homeostasis (canonical function) are the ubiquitin–proteasome system and chaperone-mediated autophagy. The CS has also noncanonical functions, for instance, modulation of the IS with induction of proinflammatory cytokines. This deserves investigation because it may be at the core of neuroinflammation, and elucidation of its mechanism will open roads toward developing efficacious treatments centered on molecular chaperones (i.e., chaperonotherapy). Here, we discuss information available on the role of three members of the CS—heat shock protein (Hsp)60, Hsp70, and Hsp90—in IS modulation and neuroinflammation. These three chaperones occur intra- and extracellularly, with the latter being the most likely involved in neuroinflammation because they can interact with the IS. We discuss some of the interactions, their consequences, and the molecules involved but many aspects are still incompletely elucidated, and we hope that this review will encourage research based on the data presented to pave the way for the development of chaperonotherapy. This may consist of blocking a chaperone that promotes destructive neuroinflammation or replacing or boosting a defective chaperone with cytoprotective activity against neurodegeneration.

scholarly journals Tuning the proteasome to brighten the end of the journey

2016 ◽  
Vol 311 (5) ◽  
pp. C793-C804 ◽  
Author(s):  
Thibault Mayor ◽  
Michal Sharon ◽  
Michael H. Glickman
Keyword(s):  
Cell Cycle Progression ◽  
Ubiquitin Proteasome System ◽  
Proteasome Activity ◽  
Cellular Proteins ◽  
Regulatory Mechanisms ◽  
Protein Homeostasis ◽  
Cycle Progression ◽  
Cellular Processes ◽  
Age Related ◽  
Ubiquitin Proteasome

Degradation by the proteasome is the fate for a large portion of cellular proteins, and it plays a major role in maintaining protein homeostasis, as well as in regulating many cellular processes like cell cycle progression. A decrease in proteasome activity has been linked to aging and several age-related neurodegenerative pathologies and highlights the importance of the ubiquitin proteasome system regulation. While the proteasome has been traditionally viewed as a constitutive element of proteolysis, major studies have highlighted how different regulatory mechanisms can impact its activity. Importantly, alterations of proteasomal activity may have major impacts for its function and in therapeutics. On one hand, increasing proteasome activity could be beneficial to prevent the age-related downfall of protein homeostasis, whereas inhibiting or reducing its activity can prevent the proliferation of cancer cells.

scholarly journals Role of Eicosanoids in Regulating the Ubiquitin Proteasome System and Proteostasis

2020 ◽  
Vol 1 (1) ◽  
Author(s):  
Amanpreet Kaur
Keyword(s):  
Degradation Mechanism ◽  
Protein A ◽  
Chimeric Protein ◽  
Ubiquitin Proteasome System ◽  
Protein Homeostasis ◽  
Intercellular Signaling ◽  
Wild Type ◽  
Signaling Mechanisms ◽  
Ubiquitin Proteasome

The ubiquitin proteasome system (UPS) is a protein degradation mechanism in eukaryotes crucial to maintaining protein homeostasis, or proteostasis. There are tissue-specific differences in UPS activity and proteostasis, but the intercellular signaling mechanisms that mediate these differences are not well understood. This work examines eicosanoid signaling molecules—which are derived from polyunsaturated fatty acids (PUFAs)—and their role in proteostasis regulation, particularly the UPS. A reporter transgene that expresses the UbG76V-GFP chimeric protein, a metastable substrate for the UPS, is used in Caenorhabditis elegans epithelial cells to monitor the level of UPS activity. In wild-type nematodes, UbG76V-GFP levels remain high through 24 hours post L4 stage (L4+24). Then, levels decrease significantly due to increased UPS activity as the animals age and develop 48 hours past L4 (L4+48). Mutants for fat-1, a desaturase enzyme that converts ω-6 PUFAs to ω-3 PUFAs, exhibited elevated UbG76V-GFP turnover in the hypodermis even at the L4+24 stage, suggesting that either ω-6 PUFAs (or their eicosanoid derivatives) promote UPS activity or ω-3 PUFAs (or their eicosanoid derivatives) inhibit UPS activity. In the intestine, mutants for fat-1 showed reduced UbG76V-GFP turnover at the L4+24 and L4+48 life stages. Additionally, mutants for emb-8—an NADPH reductase needed to convert PUFAs into eicosanoids—also showed reduced UbG76V-GFP turnover in the hypodermis even at the L4+48 stage. These results suggest that elements of the eicosanoid signaling pathway, including ω-6 PUFAs and their derivatives, significantly contribute to regulation of the UPS and proteostasis.

scholarly journals Ubiquitin-dependent and independent roles of SUMO in proteostasis

2016 ◽  
Vol 311 (2) ◽  
pp. C284-C296 ◽  
Author(s):  
Frauke Liebelt ◽  
Alfred C. O. Vertegaal
Keyword(s):  
Treatment Options ◽  
Ubiquitin Proteasome System ◽  
Protein Homeostasis ◽  
Protein Signaling ◽  
New Production ◽  
Polyglutamine Disorders ◽  
Novel Treatment ◽  
Ubiquitin Proteasome ◽  
Multiple Levels

Cellular proteomes are continuously undergoing alterations as a result of new production of proteins, protein folding, and degradation of proteins. The proper equilibrium of these processes is known as proteostasis, implying that proteomes are in homeostasis. Stress conditions can affect proteostasis due to the accumulation of misfolded proteins as a result of overloading the degradation machinery. Proteostasis is affected in neurodegenerative diseases like Alzheimer's disease, Parkinson's disease, and multiple polyglutamine disorders including Huntington's disease. Owing to a lack of proteostasis, neuronal cells build up toxic protein aggregates in these diseases. Here, we review the role of the ubiquitin-like posttranslational modification SUMO in proteostasis. SUMO alone contributes to protein homeostasis by influencing protein signaling or solubility. However, the main contribution of SUMO to proteostasis is the ability to cooperate with, complement, and balance the ubiquitin-proteasome system at multiple levels. We discuss the identification of enzymes involved in the interplay between SUMO and ubiquitin, exploring the complexity of this crosstalk which regulates proteostasis. These enzymes include SUMO-targeted ubiquitin ligases and ubiquitin proteases counteracting these ligases. Additionally, we review the role of SUMO in brain-related diseases, where SUMO is primarily investigated because of its role during formation of aggregates, either independently or in cooperation with ubiquitin. Detailed understanding of the role of SUMO in these diseases could lead to novel treatment options.

scholarly journals Nuclear polyglutamine-containing protein aggregates as active proteolytic centers

2008 ◽  
Vol 180 (4) ◽  
pp. 697-704 ◽  
Author(s):  
Min Chen ◽  
Lena Singer ◽  
Andrea Scharf ◽  
Anna von Mikecz
Keyword(s):  
Biological Function ◽  
Local Level ◽  
Sodium Dodecyl ◽  
Protein Aggregates ◽  
Ubiquitin Proteasome System ◽  
Cellular Responses ◽  
Regulatory Mechanisms ◽  
Large Protein ◽  
Ubiquitin Proteasome ◽  
Dependent Protein

Protein aggregates and nuclear inclusions (NIs) containing components of the ubiquitin–proteasome system (UPS), expanded polyglutamine (polyQ) proteins, and transcriptional coactivators characterize cellular responses to stress and are hallmarks of neurodegenerative diseases. The biological function of polyQ-containing aggregates is unknown. To analyze proteasomal activity within such aggregates, we present a nanoparticle (NP)-based method that enables controlled induction of sodium dodecyl sulfate–resistant inclusions of endogenous nuclear proteins while normal regulatory mechanisms remain in place. Consistent with the idea that the UPS maintains quality control, inhibition of proteasomal proteolysis promotes extra large protein aggregates (1.4–2 μm), whereas formation of NP-induced NIs is found to be inversely correlated to proteasome activation. We show that global proteasomal proteolysis increases in NP-treated nuclei and, on the local level, a subpopulation of NIs overlaps with focal domains of proteasome-dependent protein degradation. These results suggest that inclusions in the nucleus constitute active proteolysis modules that may serve to concentrate and decompose damaged, malfolded, or misplaced proteins.

scholarly journals Immunoproteasome Function in Normal and Malignant Hematopoiesis

Cells ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 1577
Author(s):  
Nuria Tubío-Santamaría ◽  
Frédéric Ebstein ◽  
Florian H. Heidel ◽  
Elke Krüger
Keyword(s):  
Proteasome Inhibition ◽  
Ubiquitin Proteasome System ◽  
Hematologic Malignancies ◽  
Protein Homeostasis ◽  
Efficacy And Safety ◽  
Hematopoietic System ◽  
Oxidized Proteins ◽  
Attractive Therapeutic Target ◽  
Ubiquitin Proteasome ◽  
Early Phases

The ubiquitin–proteasome system (UPS) is a central part of protein homeostasis, degrading not only misfolded or oxidized proteins but also proteins with essential functions. The fact that a healthy hematopoietic system relies on the regulation of protein homeostasis and that alterations in the UPS can lead to malignant transformation makes the UPS an attractive therapeutic target for the treatment of hematologic malignancies. Herein, inhibitors of the proteasome, the last and most important component of the UPS enzymatic cascade, have been approved for the treatment of these malignancies. However, their use has been associated with side effects, drug resistance, and relapse. Inhibitors of the immunoproteasome, a proteasomal variant constitutively expressed in the cells of hematopoietic origin, could potentially overcome the encountered problems of non-selective proteasome inhibition. Immunoproteasome inhibitors have demonstrated their efficacy and safety against inflammatory and autoimmune diseases, even though their development for the treatment of hematologic malignancies is still in the early phases. Various immunoproteasome inhibitors have shown promising preliminary results in pre-clinical studies, and one inhibitor is currently being investigated in clinical trials for the treatment of multiple myeloma. Here, we will review data on immunoproteasome function and inhibition in hematopoietic cells and hematologic cancers.

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.

Sign in / Sign up

Export Citation Format

Share Document