Ferroptosis is a form of cell death elicited by an imbalance in intracellular iron concentrations, leading to enhanced lipid peroxidation. In neurological disorders, both oxidative stress and mitochondrial damage can contribute to ferroptosis, resulting in nerve cell dysfunction and death. The ubiquitin-proteasome system (UPS) refers to a cellular pathway in which specific proteins are tagged with ubiquitin for recognition and degradation by the proteasome. In neurological conditions, the UPS plays a significant role in regulating ferroptosis. In this review, we outline how the UPS regulates iron metabolism, ferroptosis, and their interplay in neurological diseases. In addition, we discuss the future application of small-molecule inhibitors and identify potential drug targets. Further investigation into the mechanisms of UPS-mediated ferroptosis will provide novel insights and strategies for therapeutic interventions and clinical applications in neurological diseases.
Ferroptosis/physiology* ; Humans ; Proteasome Endopeptidase Complex/metabolism* ; Nervous System Diseases/metabolism* ; Animals ; Ubiquitin/metabolism* ; Iron/metabolism*

The N-end rule pathway is a protein degradation pathway mediated by the ubiquitin-proteasome system, which specifically targets and degrades target proteins by recognizing specific residues at the N-terminus of the proteins. The residues which play a crucial role in the N-end rule pathway are called degrons, also known as N-degrons, as they are usually unstable at the N-terminal end of the protein. Currently, several N-end rule pathways have been identified in the eukaryotes, including the Arg/N-end rule, Ac/N-end rule, and Pro/N-end rule pathways, as well as the recently discovered Gly/N-end rule pathway. The Ac/N-end rule pathway targets proteins containing N-terminal acetylation (Nt-acetylation) residues. The Arg/N-end rule pathway, on the other hand, targets certain unacetylated residues and involves N-terminal arginylation. For proteins with N-terminal proline (Pro) and glycine (Gly) residues, they are neither modified by acetylation nor recognized through the Arg/N-end rule pathway. Therefore, these proteins are primarily recognized and degraded through the Pro/N-end rule pathway and the Gly/N-end rule pathway. The regulation of specific proteins through N-end rule pathway-mediated degradation plays an important role in numerous physiological and pathological processes, such as cardiovascular development, neurogenesis, meiosis, spermatogenesis, HPV infection, and cell apoptosis. In this review, we summarize the role and mechanisms of several known N-end rule pathways and discuss their relationship with certain diseases. As an independent protein degradation system, the N-end rule pathways still hold countless biological secrets waiting for exploring. The comprehensive understanding of these pathways could potentially uncover novel therapeutic targets for various diseases.
Humans ; Proteolysis ; Animals ; Proteasome Endopeptidase Complex/physiology* ; Acetylation ; Proteins/metabolism* ; Protein Processing, Post-Translational ; Ubiquitin/metabolism*

The maintenance of skeletal muscle quality involves various signal pathways that interact with each other. Under normal physiological conditions, these intersecting signal pathways regulate and coordinate the hypertrophy and atrophy of skeletal muscles, balancing the protein synthesis and degradation of muscle. When the total rate of protein synthesis exceeds that of protein degradation, the muscle gradually becomes enlarged, while when the total rate of protein synthesis is lower than that of protein degradation, the muscle shrinks. Myocyte atrophy mainly involves two protein degradation pathways, namely ubiquitin-proteasome and autophagy-lysosome. Protein degradation pathway is activated during muscle atrophy, resulting in the loss of muscle mass. Muscle atrophy can occur under various conditions such as malnutrition, aging and cachexia. Skeletal muscle atrophy caused by orthopedic diseases mainly includes disuse muscular atrophy caused by fracture and denervation muscular atrophy. The signal pathways that control and coordinate protein synthesis and degradation in skeletal muscle include insulin-like growth factor 1 (IGF1)-Akt-mammalian target of rapamycin (mTOR), myostatin-activin A-Smad, G protein α inhibitory peptide 2 (Gαi2)-PKC, nuclear factor κB (NF-κB), ectodysplasin A2 receptor (EDA2R)-NF-κB inducing kinase (NIK) and mitogen-activated protein kinase (MAPK) pathways. This paper provides a comprehensive review of the protein degradation pathways in skeletal muscle atrophy and the associated signal pathways regulating protein degradation in muscular atrophy.
Humans ; Muscular Atrophy/etiology* ; Muscle, Skeletal/pathology* ; Signal Transduction ; Animals ; Insulin-Like Growth Factor I/metabolism* ; Myostatin/physiology* ; TOR Serine-Threonine Kinases/metabolism* ; Autophagy/physiology* ; NF-kappa B/metabolism* ; Proteolysis ; Proteasome Endopeptidase Complex/physiology*

The clinical treatment of joint contracture due to immobilization remains difficult. The pathological changes of muscle tissue caused by immobilization-induced joint contracture include disuse skeletal muscle atrophy and skeletal muscle tissue fibrosis. The proteolytic pathways involved in disuse muscle atrophy include the ubiquitin-proteasome-dependent pathway, caspase system pathway, matrix metalloproteinase pathway, Ca-dependent pathway and autophagy-lysosomal pathway. The important biological processes involved in skeletal muscle fibrosis include intermuscular connective tissue thickening caused by transforming growth factor-β1 and an anaerobic environment within the skeletal muscle leading to the induction of hypoxia-inducible factor-1α. This article reviews the progress made in understanding the pathological processes involved in immobilization-induced muscle contracture and the currently available treatments. Understanding the mechanisms involved in immobilization-induced contracture of muscle tissue should facilitate the development of more effective treatment measures for the different mechanisms in the future.
Atrophy ; Autophagy ; Calcium ; metabolism ; Caspases ; metabolism ; Connective Tissue ; metabolism ; pathology ; Contracture ; etiology ; metabolism ; pathology ; therapy ; Fibrosis ; Humans ; Immobilization ; adverse effects ; Joints ; Lysosomes ; metabolism ; Matrix Metalloproteinases ; metabolism ; Muscle, Skeletal ; metabolism ; pathology ; Proteasome Endopeptidase Complex ; metabolism ; Proteolysis ; Signal Transduction ; physiology ; Transforming Growth Factor beta1 ; metabolism ; Ubiquitin ; metabolism

More than 80% of all cases of deafness are related to the death or degeneration of cochlear hair cells and the associated spiral ganglion neurons, and a lack of regeneration of these cells leads to permanent hearing loss. Therefore, the regeneration of lost hair cells is an important goal for the treatment of deafness. Atoh1 is a basic helix-loop-helix (bHLH) transcription factor that is critical in both the development and regeneration of cochlear hair cells. Atoh1 is transcriptionally regulated by several signaling pathways, including Notch and Wnt signalings. At the post-translational level, it is regulated through the ubiquitin-proteasome pathway. In vitro and in vivo studies have revealed that manipulation of these signaling pathways not only controls development, but also leads to the regeneration of cochlear hair cells after damage. Recent progress toward understanding the signaling networks involved in hair cell development and regeneration has led to the development of new strategies to replace lost hair cells. This review focuses on our current understanding of the signaling pathways that regulate Atoh1 in the cochlea.
Basic Helix-Loop-Helix Transcription Factors/physiology* ; Cell Differentiation ; Cochlea/physiology* ; Hair Cells, Auditory/physiology* ; Hearing Loss/etiology* ; Humans ; Proteasome Endopeptidase Complex/physiology* ; Signal Transduction/physiology* ; Transcription Factors/physiology* ; Ubiquitin/metabolism* ; Wnt Signaling Pathway ; beta Catenin/physiology*

The ubiquitin-proteasome system (UPS) is a proteasome system widely present in the human body, which is composed of ubiquitin (Ub), ubiquitin activating enzymes (E1), ubiquitin conjugating enzymes (E2), ubiquitin protein ligases (E3), 26S proteasome, and deubiquitinating enzymes (DUBs) and involved in cell cycle regulation, immune response, signal transduction, DNA repair as well as protein degradation. Sperm DNA is vulnerable to interference or damage in the progression of chromosome association and homologous recombination. Recent studies show that UPS participates in DNA repair in spermatogenesis by modulating DNA repair enzymes via ubiquitination, assisting in the identification of DNA damage sites, raising damage repair-related proteins, initiating the DNA repair pathway, maintaining chromosome stability, and ensuring the normal process of spermatogenesis.
Cell Cycle Proteins ; physiology ; DNA Damage ; DNA Repair ; physiology ; Humans ; Male ; Proteasome Endopeptidase Complex ; physiology ; Signal Transduction ; physiology ; Spermatogenesis ; physiology ; Spermatozoa ; Ubiquitin ; physiology ; Ubiquitin-Conjugating Enzymes ; physiology ; Ubiquitin-Protein Ligases ; physiology ; Ubiquitination

PURPOSE: To investigate the effects of resveratrol on the expression of hypoxia-inducible factor 1alpha (HIF-1alpha) and vascular endothelial growth factor (VEGF) in human adult retinal pigment epithelial (ARPE-19) cells, and on experimental choroidal neovascularization (CNV) in mice. MATERIALS AND METHODS: ARPE-19 cells were treated with different concentrations of resveratrol and then incubated under hypoxic conditions with subsequent evaluation of cell viability, expression of HIF-1alpha, and expression of VEGF. The effects of resveratrol on the synthesis and degradation of hypoxia-induced HIF-1alpha were evaluated using inhibitors of the PI3K/Akt/mTOR and the ubiquitin proteasome pathways. In animal studies, CNV lesions were induced in C57BL/6 mice by laser photocoagulation. After 7 days of oral administration of resveratrol or vehicle, which began one day after CNV induction, image analysis was used to measure CNV areas on choroidal flat mounts stained with isolectin IB4. RESULTS: In ARPE-19 cells, resveratrol significantly inhibited HIF-1alpha and VEGF in a dose-dependent manner, by blocking the PI3K/Akt/mTOR signaling pathway and by promoting proteasomal HIF-1alpha degradation. In mice experiments, orally administered resveratrol significantly inhibited CNV growth in a dose-dependent manner. CONCLUSION: Resveratrol may have therapeutic value in the management of diseases involving pathological neovascularization.
Adult ; Animals ; Anoxia/metabolism/physiopathology ; Cell Survival/drug effects ; Choroidal Neovascularization/*metabolism/pathology ; Humans ; Hypoxia-Inducible Factor 1, alpha Subunit/*drug effects/metabolism ; Mice ; Mice, Inbred C57BL ; Phosphatidylinositol 3-Kinases/antagonists & inhibitors/*physiology ; Proteasome Endopeptidase Complex ; Proto-Oncogene Proteins c-akt/antagonists & inhibitors/*physiology ; Retinal Pigment Epithelium/*drug effects/metabolism ; Signal Transduction ; Stilbenes/administration & dosage/*pharmacology ; TOR Serine-Threonine Kinases/antagonists & inhibitors/*physiology ; Ubiquitin ; Vascular Endothelial Growth Factor A/*drug effects/metabolism

Hypoxia-inducible factor 1alpha (HIF-1alpha), which transactivates a variety of hypoxia-induced genes, is rapidly degraded under nomoxia through the hydroxylation-ubiquitination-proteasome pathway. In this study, we addressed how HIF-1alpha is stabilized by proteasome inhibitors. The ubiquitin pool was rapidly reduced after proteasome inhibition, followed by the accumulation of non-ubiquitinated HIF-1alpha. The poly-ubiquitination of HIF-1alpha was resumed by restoration of free ubiquitin, which suggests that the HIF-1alpha stabilization under proteasome inhibition is attributed to depletion of the free ubiquitin pool. Ni2+ and Zn2+ also stabilized HIF-1alpha with depletion of the free ubiquitin pool and these effects of metal ions were attenuated by restoration of free ubiquitin. Ni2+ and Zn2+ may disturb the recycling of free ubiquitin, as MG132 does. Based on these results, the state of the ubiquitin pool seems to be another critical factor determining the cellular level of HIF-1alpha.
Cell Hypoxia/physiology ; Cell Line, Tumor ; HCT116 Cells ; HEK293 Cells ; Humans ; Hypoxia-Inducible Factor 1, alpha Subunit/biosynthesis/*metabolism ; Leupeptins/pharmacology ; Nickel/chemistry ; Proteasome Endopeptidase Complex/*metabolism ; Proteasome Inhibitors/*pharmacology ; Ubiquitin/*metabolism ; Ubiquitination/*physiology ; Up-Regulation ; Zinc/chemistry

The p26, a multifunctional ubiquitin-binding protein, has been proposed to be involved in protein degradation as a component within the ubiquitin-proteasome and autophagy-lysosome systems. As a scaffolding protein with several different kinds of protein-protein interaction domains, p62 mediates various cellular functions. Importantly, p62 plays a critical role in cell's selective autophagy and oxidative stress response, which are associated with the pathogenesis of several human diseases. In this review, we describe the structure of p62 and the mechanism of connection between p62 and ubiquitin-proteasome system/autophagy, so as to provide some perspectives on p62 research.
Adaptor Proteins, Signal Transducing ; physiology ; Autophagy ; Humans ; Oxidative Stress ; Proteasome Endopeptidase Complex ; Protein Interaction Domains and Motifs ; Proteolysis ; Ubiquitin

In order to compete the antiviral effects of the host cell in the process of infection, ORFV(known as Orf virus) relies on a series of functional genes developed through long-term population evolution, such as interferon resistance genes, Bcl-2 protein genes and cell cycle inhibitor gene and so on, with these weapons this virus is able to effectively counteract immune clearance and immune regulation from a host cell. Concurrently, ORFV also focuses on exploiting signal transduction pathways of the ubiquitin-proteasome system(UPS), circumvents the intracellular signal transduction and CD8+ T activation, for shielding virus particles towards maturation and releasing outside. This review introduced inner link between the UPS of host cell and intervention mechanism by virus, and analyzed the key roles of certains components in UPS, these all together showed the evolution tendency of ORFV that was involved in the designing of inhibition to immune response and for intracellular immune escape upon the selection pressure in host cell infected.
Animals ; Ecthyma, Contagious ; enzymology ; virology ; Host-Pathogen Interactions ; Humans ; Orf virus ; genetics ; physiology ; Proteasome Endopeptidase Complex ; metabolism ; Ubiquitin ; metabolism