scholarly journals Implications of FBXW7 in Neurodevelopment and Neurodegeneration: Molecular Mechanisms and Therapeutic Potential

2021 ◽  
Vol 15 ◽  
Author(s):  
Yu Yang ◽  
Xuan Zhou ◽  
Xinpeng Liu ◽  
Ruying Song ◽  
Yiming Gao ◽  
...  
Keyword(s):  
Neurodegenerative Disorders ◽  
Molecular Mechanisms ◽  
Therapeutic Potential ◽  
Ubiquitin Proteasome System ◽  
Cellular Protein ◽  
Protein Homeostasis ◽  
Potential Therapeutic Target ◽  
Cellular Processes ◽  
Wide Range ◽  
Ubiquitin Proteasome

The ubiquitin-proteasome system (UPS) mediated protein degradation is crucial to maintain quantitive and functional homeostasis of diverse proteins. Balanced cellular protein homeostasis controlled by UPS is fundamental to normal neurological functions while impairment of UPS can also lead to some neurodevelopmental and neurodegenerative disorders. Functioning as the substrate recognition component of the SCF-type E3 ubiquitin ligase, FBXW7 is essential to multiple aspects of cellular processes via targeting a wide range of substrates for proteasome-mediated degradation. Accumulated evidence shows that FBXW7 is fundamental to neurological functions and especially implicated in neurodevelopment and the nosogenesis of neurodegeneration. In this review, we describe general features of FBXW7 gene and proteins, and mainly present recent findings that highlight the vital roles and molecular mechanisms of FBXW7 in neurodevelopment such as neurogenesis, myelination and cerebral vasculogenesis and in the pathogenesis of some typical neurodegenerative disorders such as Alzheimer’s disease, Parkinson’s disease and Huntington’s disease. Additionally, we also provide a prospect on focusing FBXW7 as a potential therapeutic target to rescue neurodevelopmental and neurodegenerative impairment.

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 A Nut for Every Bolt: Subunit-Selective Inhibitors of the Immunoproteasome and Their Therapeutic Potential

Cells ◽  
2021 ◽  
Vol 10 (8) ◽  
pp. 1929
Author(s):  
Eva M. Huber ◽  
Michael Groll
Keyword(s):  
Cell Cycle Progression ◽  
Therapeutic Potential ◽  
Cell Signalling ◽  
Selective Inhibition ◽  
Ubiquitin Proteasome System ◽  
Cellular Processes ◽  
Chemical Structures ◽  
Phase Ii Clinical Trials ◽  
Ubiquitin Proteasome ◽  
Recent Trends

At the heart of the ubiquitin–proteasome system, the 20S proteasome core particle (CP) breaks down the majority of intracellular proteins tagged for destruction. Thereby, the CP controls many cellular processes including cell cycle progression and cell signalling. Inhibitors of the CP can suppress these essential biological pathways, resulting in cytotoxicity, an effect that is beneficial for the treatment of certain blood cancer patients. During the last decade, several preclinical studies demonstrated that selective inhibition of the immunoproteasome (iCP), one of several CP variants in mammals, suppresses autoimmune diseases without inducing toxic side effects. These promising findings led to the identification of natural and synthetic iCP inhibitors with distinct chemical structures, varying potency and subunit selectivity. This review presents the most prominent iCP inhibitors with respect to possible scientific and medicinal applications, and discloses recent trends towards pan-immunoproteasome reactive inhibitors that cumulated in phase II clinical trials of the lead compound KZR-616 for chronic inflammations.

scholarly journals A Homeostatic Shift Facilitates Endoplasmic Reticulum Proteostasis through Transcriptional Integration of Proteostatic Stress Response Pathways

2016 ◽  
Vol 37 (4) ◽  
Author(s):  
Liam Baird ◽  
Tadayuki Tsujita ◽  
Eri H. Kobayashi ◽  
Ryo Funayama ◽  
Takeshi Nagashima ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Transcriptional Regulation ◽  
Ubiquitin Proteasome System ◽  
Conditional Knockout ◽  
Protein Homeostasis ◽  
Knockout Mouse Model ◽  
Conditional Knockout Mouse ◽  
Wide Range ◽  
Ubiquitin Proteasome ◽  
Inducible Systems

ABSTRACT Eukaryotic cells maintain protein homeostasis through the activity of multiple basal and inducible systems, which function in concert to allow cells to adapt to a wide range of environmental conditions. Although the transcriptional programs regulating individual pathways have been studied in detail, it is not known how the different pathways are transcriptionally integrated such that a deficiency in one pathway can be compensated by a change in an auxiliary response. One such pathway that plays an essential role in many proteostasis responses is the ubiquitin-proteasome system, which functions to degrade damaged, unfolded, or short half-life proteins. Transcriptional regulation of the proteasome is mediated by the transcription factor Nrf1. Using a conditional knockout mouse model, we found that Nrf1 regulates protein homeostasis in the endoplasmic reticulum (ER) through transcriptional regulation of the ER stress sensor ATF6. In Nrf1 conditional-knockout mice, a reduction in proteasome activity is accompanied by an ATF6-dependent downregulation of the endoplasmic reticulum-associated degradation machinery, which reduces the substrate burden on the proteasome. This indicates that Nrf1 regulates a homeostatic shift through which proteostasis in the endoplasmic reticulum and cytoplasm are coregulated based on a cell's ability to degrade proteins.

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.

Targeting Protein Degradation in Cancer Treatment

2020 ◽  
Vol 14 ◽  
Author(s):  
Imane Bjij ◽  
Ismail Hdoufane ◽  
Mahmoud Soliman ◽  
Menče Najdoska-Bogdanov ◽  
Driss Cherqaoui
Keyword(s):  
Protein Degradation ◽  
Therapeutic Potential ◽  
Ubiquitin Proteasome System ◽  
Degradation Pathway ◽  
Cellular Protein ◽  
Cellular Level ◽  
Cancerous Cell ◽  
Promising Target ◽  
Anti Cancer ◽  
Ubiquitin Proteasome

: The ubiquitin proteasome system (UPS) is a crucial protein degradation pathway that involves several enzymes to maintain cellular protein homeostasis. This system has emerged as a major drug target against certain types of cancer as a disruption at the cellular level of UPS enzyme components forces the transformation of normal cell into cancerous cell. Although enormous advancements have been achieved in the understanding of tumorigenesis, efficient cancer therapy remains a goal towards alleviating this serious health issue. Since UPS has become a promising target for anticancer therapies, herein we provide comprehensive review of the ubiquitin proteasome system as a significant process for protein degradation. Herein, the anti-cancer therapeutic potential of this pathway is also discussed.

scholarly journals Proteasomes in Protein Homeostasis of Pluripotent Stem Cells

Acta Naturae ◽  
2017 ◽  
Vol 9 (3) ◽  
pp. 39-47 ◽  
Author(s):  
А. V. Selenina ◽  
А. S. Tsimokha ◽  
А. N. Tomilin
Keyword(s):  
Stem Cells ◽  
Regenerative Medicine ◽  
Pluripotent Stem Cells ◽  
Molecular Mechanisms ◽  
Embryonic Stem ◽  
Basic Research ◽  
Ubiquitin Proteasome System ◽  
Protein Homeostasis ◽  
Cellular Processes ◽  
Induced Pluripotent

Embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) are subjects of high interest not only in basic research, but also in various applied fields, particularly, in regenerative medicine. Despite the tremendous interest to these cells, the molecular mechanisms that control protein homeostasis in these cells remain largely unknown. The ubiquitin-proteasome system (UPS) acts via post-translational protein modifications and protein degradation and, therefore, is involved in the control of virtually all cellular processes: cell cycle, self-renewal, signal transduction, transcription, translation, oxidative stress, immune response, apoptosis, etc. Therefore, studying the biological role and action mechanisms of the UPS in pluripotent cells will help to better understand the biology of cells, as well as to develop novel approaches for regenerative medicine.

scholarly journals AMPK regulates ESCRT-dependent microautophagy of proteasomes concomitant with proteasome storage granule assembly during glucose starvation

2019 ◽  
Author(s):  
Jianhui Li ◽  
Michal Breker ◽  
Morven Graham ◽  
Maya Schuldiner ◽  
Mark Hochstrasser
Keyword(s):  
Mammalian Cells ◽  
Ubiquitin Proteasome System ◽  
Protein Homeostasis ◽  
Glucose Starvation ◽  
Endosomal Sorting ◽  
Cellular Processes ◽  
Ubiquitin Proteasome ◽  
Storage Granules ◽  
Protein Deposit ◽  
Amp Activated Protein Kinase

AbstractThe ubiquitin-proteasome system regulates numerous cellular processes and is central to protein homeostasis. In proliferating yeast and many mammalian cells, proteasomes are highly enriched in the nucleus. In carbon-starved yeast, proteasomes migrate to the cytoplasm and collect in phase-separated proteasome storage granules (PSGs). PSGs dissolve and proteasomes return to the nucleus within minutes of glucose refeeding. The mechanisms by which cells regulate proteasome homeostasis under these conditions remain largely unknown. Here we show that AMP-activated protein kinase (AMPK) together with endosomal sorting complexes required for transport (ESCRTs) drive a glucose starvation-dependent microautophagy pathway that preferentially sorts aberrant proteasomes into the vacuole, thereby biasing accumulation of functional proteasomes in PSGs. The proteasome core particle (CP) and regulatory particle (RP) are regulated differently. Without AMPK, the insoluble protein deposit (IPOD) serves as an alternative site that specifically sequesters CP aggregates. Our findings reveal a novel AMPK-controlled ESCRT-mediated microautophagy mechanism in the regulation of proteasome trafficking and homeostasis under carbon starvation.

The therapeutic potential of deubiquitinating enzyme inhibitors

2010 ◽  
Vol 38 (1) ◽  
pp. 137-143 ◽  
Author(s):  
Frédéric Colland
Keyword(s):  
Anticancer Agents ◽  
Enzyme Inhibitors ◽  
Therapeutic Potential ◽  
Ubiquitin Proteasome System ◽  
Cellular Protein ◽  
Deubiquitinating Enzymes ◽  
Promising Alternative ◽  
Mantle Cell ◽  
Ubiquitin Proteasome ◽  
Ubiquitin Conjugation

Proteases play a key role in various pathological processes and several protease inhibitors are already available for treatment. DUBs (deubiquitinating enzymes) constitute one of the largest classes of human proteases and are key effectors of the ubiquitin–proteasome system. This pathway regulating cellular protein turnover has been implicated in the pathogenesis of many human diseases, including neurodegenerative disorders, viral diseases and cancer. The therapeutic efficacy of the proteasome inhibitor Velcade® (bortezomib) for treating multiple myeloma and mantle cell lymphoma establishes this system as a valid target for cancer treatment. A promising alternative to targeting the proteasome itself would be to target the upstream, ubiquitin conjugation/deconjugation system, to generate more specific, less toxic anticancer agents. Advances in small molecule-based inhibitors specifically targeting DUBs are presented in this review.

scholarly journals Regulation of Posttranscriptional Modification as a Possible Therapeutic Approach for Retinal Neuroprotection

2011 ◽  
Vol 2011 ◽  
pp. 1-8 ◽  
Author(s):  
Yoko Ozawa ◽  
Toshihide Kurihara ◽  
Kazuo Tsubota ◽  
Hideyuki Okano
Keyword(s):  
Diabetic Retinopathy ◽  
Molecular Mechanisms ◽  
Therapeutic Potential ◽  
Ubiquitin Proteasome System ◽  
Synaptic Activity ◽  
Therapeutic Approaches ◽  
New Therapeutic Approaches ◽  
Ubiquitin Proteasome

Understanding pathogenesis at the molecular level is the first step toward developing new therapeutic approaches. Here, we review the molecular mechanisms of visual dysfunction in two common diseases, innate chorioretinal inflammation and diabetic retinopathy, and the role of the ubiquitin-proteasome system (UPS) in both processes. In innate chorioretinal inflammation, interleukin-6 family ligands induce STAT3 activation in photoreceptors, which causes UPS-mediated excessive degradation of the visual substance, rhodopsin. In diabetic retinopathy, angiotensin II type 1 receptor (AT1R) signaling activates ERK in the inner layers of the retina, causing UPS-mediated excessive degradation of the synaptic vesicle protein, synaptophysin. This latter effect may decrease synaptic activity, in turn adversely affecting neuronal survival. Both mechanisms involve increased UPS activity and the subsequent excessive degradation of a protein required for visual function. Finally, we review the therapeutic potential of regulating the UPS to protect tissue function, citing examples from clinical applications in other medical fields.

scholarly journals The Ubiquitin–Proteasome System in Immune Cells

Biomolecules ◽  
2021 ◽  
Vol 11 (1) ◽  
pp. 60
Author(s):  
Gonca Çetin ◽  
Sandro Klafack ◽  
Maja Studencka-Turski ◽  
Elke Krüger ◽  
Frédéric Ebstein
Keyword(s):  
Immune Cells ◽  
Antigen Processing ◽  
Molecular Mechanisms ◽  
Inflammatory Diseases ◽  
Ubiquitin Proteasome System ◽  
Cellular Processes ◽  
Adaptive Immune ◽  
Ubiquitin Proteasome ◽  
Almost All ◽  
Lysosomal Protein

The ubiquitin–proteasome system (UPS) is the major intracellular and non-lysosomal protein degradation system. Thanks to its unique capacity of eliminating old, damaged, misfolded, and/or regulatory proteins in a highly specific manner, the UPS is virtually involved in almost all aspects of eukaryotic life. The critical importance of the UPS is particularly visible in immune cells which undergo a rapid and profound functional remodelling upon pathogen recognition. Innate and/or adaptive immune activation is indeed characterized by a number of substantial changes impacting various cellular processes including protein homeostasis, signal transduction, cell proliferation, and antigen processing which are all tightly regulated by the UPS. In this review, we summarize and discuss recent progress in our understanding of the molecular mechanisms by which the UPS contributes to the generation of an adequate immune response. In this regard, we also discuss the consequences of UPS dysfunction and its role in the pathogenesis of recently described immune disorders including cancer and auto-inflammatory diseases.

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