scholarly journals More Than Just Cleaning: Ubiquitin-Mediated Proteolysis in Fungal Pathogenesis

2021 ◽  
Vol 11 ◽  
Author(s):  
Chengjun Cao ◽  
Chaoyang Xue
Keyword(s):  
Stress Responses ◽  
Fungal Infections ◽  
Proteasome Inhibitors ◽  
Field Research ◽  
Pathogenic Fungi ◽  
Ubiquitin Proteasome System ◽  
Fungal Pathogenesis ◽  
Regulatory Function ◽  
Pathogenic Factors ◽  
Ubiquitin Proteasome

Ubiquitin-proteasome mediated protein turnover is an important regulatory mechanism of cellular function in eukaryotes. Extensive studies have linked the ubiquitin-proteasome system (UPS) to human diseases, and an array of proteasome inhibitors have been successfully developed for cancer therapy. Although still an emerging field, research on UPS regulation of fungal development and virulence has been rapidly advancing and has generated considerable excitement in its potential as a target for novel drugs. In this review, we summarize UPS composition and regulatory function in pathogenic fungi, especially in stress responses, host adaption, and fungal pathogenesis. Emphasis will be given to UPS regulation of pathogenic factors that are important for fungal pathogenesis. We also discuss future potential therapeutic strategies for fungal infections based on targeting UPS pathways.

scholarly journals Fungal Secondary Metabolites as Inhibitors of the Ubiquitin–Proteasome System

2021 ◽  
Vol 22 (24) ◽  
pp. 13309
Author(s):  
Magdalena Staszczak
Keyword(s):  
Secondary Metabolites ◽  
Control Function ◽  
Cell Cycle Control ◽  
Regulation Of Gene Expression ◽  
Proteasome Inhibitors ◽  
Ubiquitin Proteasome System ◽  
Regulatory Function ◽  
Deubiquitinating Enzymes ◽  
Ubiquitin Proteasome ◽  
Fungal Secondary Metabolites

The ubiquitin–proteasome system (UPS) is the major non-lysosomal pathway responsible for regulated degradation of intracellular proteins in eukaryotes. As the principal proteolytic pathway in the cytosol and the nucleus, the UPS serves two main functions: the quality control function (i.e., removal of damaged, misfolded, and functionally incompetent proteins) and a major regulatory function (i.e., targeted degradation of a variety of short-lived regulatory proteins involved in cell cycle control, signal transduction cascades, and regulation of gene expression and metabolic pathways). Aberrations in the UPS are implicated in numerous human pathologies such as cancer, neurodegenerative disorders, autoimmunity, inflammation, or infectious diseases. Therefore, the UPS has become an attractive target for drug discovery and development. For the past two decades, much research has been focused on identifying and developing compounds that target specific components of the UPS. Considerable effort has been devoted to the development of both second-generation proteasome inhibitors and inhibitors of ubiquitinating/deubiquitinating enzymes. With the feature of unique structure and bioactivity, secondary metabolites (natural products) serve as the lead compounds in the development of new therapeutic drugs. This review, for the first time, summarizes fungal secondary metabolites found to act as inhibitors of the UPS components.

scholarly journals ATP13A2 Regulates Cellular α-Synuclein Multimerization, Membrane Association, and Externalization

2021 ◽  
Vol 22 (5) ◽  
pp. 2689
Author(s):  
Jianmin Si ◽  
Chris Van den Haute ◽  
Evy Lobbestael ◽  
Shaun Martin ◽  
Sarah van Veen ◽  
...  
Keyword(s):  
Membrane Integrity ◽  
Ubiquitin Proteasome System ◽  
Regulatory Function ◽  
Membrane Association ◽  
Loss Of Function ◽  
Atypical Form ◽  
Polyamine Transport ◽  
Independent Functions ◽  
Ubiquitin Proteasome ◽  
The Impact

ATP13A2, a late endo-/lysosomal polyamine transporter, is implicated in a variety of neurodegenerative diseases, including Parkinson’s disease and Kufor–Rakeb syndrome, an early-onset atypical form of parkinsonism. Loss-of-function mutations in ATP13A2 result in lysosomal deficiency as a consequence of impaired lysosomal export of the polyamines spermine/spermidine. Furthermore, accumulating evidence suggests the involvement of ATP13A2 in regulating the fate of α-synuclein, such as cytoplasmic accumulation and external release. However, no consensus has yet been reached on the mechanisms underlying these effects. Here, we aimed to gain more insight into how ATP13A2 is linked to α-synuclein biology in cell models with modified ATP13A2 activity. We found that loss of ATP13A2 impairs lysosomal membrane integrity and induces α-synuclein multimerization at the membrane, which is enhanced in conditions of oxidative stress or exposure to spermine. In contrast, overexpression of ATP13A2 wildtype (WT) had a protective effect on α-synuclein multimerization, which corresponded with reduced αsyn membrane association and stimulation of the ubiquitin-proteasome system. We also found that ATP13A2 promoted the secretion of α-synuclein through nanovesicles. Interestingly, the catalytically inactive ATP13A2 D508N mutant also affected polyubiquitination and externalization of α-synuclein multimers, suggesting a regulatory function independent of the ATPase and transport activity. In conclusion, our study demonstrates the impact of ATP13A2 on α-synuclein multimerization via polyamine transport dependent and independent functions.

scholarly journals Ubiquitination and Ubiquitin-Like Modifications in Multiple Myeloma: Biology and Therapy

Cancers ◽  
2020 ◽  
Vol 12 (12) ◽  
pp. 3764
Author(s):  
Matthias Wirth ◽  
Markus Schick ◽  
Ulrich Keller ◽  
Jan Krönke
Keyword(s):  
Multiple Myeloma ◽  
Translational Regulation ◽  
Proteasome Inhibitors ◽  
Ubiquitin Proteasome System ◽  
Organ Damage ◽  
Post Translational Modifications ◽  
Damage Repair ◽  
Ubiquitin Proteasome ◽  
New Treatments ◽  
Effective Drugs

Multiple myeloma is a genetically heterogeneous plasma cell malignancy characterized by organ damage and a massive production of (in-)complete monoclonal antibodies. Coping with protein homeostasis and post-translational regulation is therefore essential for multiple myeloma cells to survive. Furthermore, post-translational modifications such as ubiquitination and SUMOylation play key roles in essential pathways in multiple myeloma, including NFκB signaling, epigenetic regulation, as well as DNA damage repair. Drugs modulating the ubiquitin–proteasome system, such as proteasome inhibitors and thalidomide analogs, are approved and highly effective drugs in multiple myeloma. In this review, we focus on ubiquitin and ubiquitin-like modifications in the biology and current developments of new treatments for multiple myeloma.

scholarly journals Regulation of Ubiquitin-Proteasome System–mediated Degradation by Cytosolic Stress

2007 ◽  
Vol 18 (11) ◽  
pp. 4279-4291 ◽  
Author(s):  
Sean M. Kelly ◽  
Judy K. VanSlyke ◽  
Linda S. Musil
Keyword(s):  
Heat Shock ◽  
Secretory Pathway ◽  
Proteasome Inhibitors ◽  
Ubiquitin Proteasome System ◽  
Transmembrane Conductance Regulator ◽  
Transmembrane Conductance ◽  
Junction Protein ◽  
Ubiquitin Proteasome ◽  
Gap Junction Protein ◽  
Cystic Fibrosis Transmembrane

ER-associated, ubiquitin-proteasome system (UPS)-mediated degradation of the wild-type (WT) gap junction protein connexin32 (Cx32) is inhibited by mild forms of cytosolic stress at a step before its dislocation into the cytosol. We show that the same conditions (a 30-min, 42°C heat shock or oxidative stress induced by arsenite) also reduce the endoplasmic reticulum (ER)-associated turnover of disease-causing mutants of Cx32 and the cystic fibrosis transmembrane conductance regulator (CFTR), as well as that of WT CFTR and unassembled Ig light chain. Stress-stabilized WT Cx32 and CFTR, but not the mutant/unassembled proteins examined, could traverse the secretory pathway. Heat shock also slowed the otherwise rapid UPS-mediated turnover of the cytosolic proteins myoD and GFPu, but not the degradation of an ubiquitination-independent construct (GFP-ODC) closely related to the latter. Analysis of mutant Cx32 from cells exposed to proteasome inhibitors and/or cytosolic stress indicated that stress reduces degradation at the level of substrate polyubiquitination. These findings reveal a new link between the cytosolic stress-induced heat shock response, ER-associated degradation, and polyubiquitination. Stress-denatured proteins may titer a limiting component of the ubiquitination machinery away from pre-existing UPS substrates, thereby sparing the latter from degradation.

scholarly journals Inhibition of the Ubiquitin-Proteasome System Affects Influenza A Virus Infection at a Postfusion Step

2010 ◽  
Vol 84 (18) ◽  
pp. 9625-9631 ◽  
Author(s):  
Ivy Widjaja ◽  
Erik de Vries ◽  
Donna M. Tscherne ◽  
Adolfo García-Sastre ◽  
Peter J. M. Rottier ◽  
...  
Keyword(s):  
Influenza A Virus ◽  
Influenza A ◽  
Rna Synthesis ◽  
Proteasome Inhibitors ◽  
Ubiquitin Proteasome System ◽  
Bafilomycin A1 ◽  
Virus Like Particle ◽  
Viral Particles ◽  
Removal Experiments ◽  
Ubiquitin Proteasome

ABSTRACT We have demonstrated that influenza A virus (IAV) RNA synthesis depends on the ubiquitin-proteasome system. IAV replication was reduced both by proteasome inhibitors and in E36ts20 cells, which contain the thermolabile ubiquitin-activating enzyme E1. While virus entry was not affected in E36ts20 cells, the proteasome inhibitor MG132 retained viral particles in the cytoplasm. Addition-removal experiments of MG132 in combination with bafilomycin A1, a well-established inhibitor of IAV entry and fusion, showed that MG132 affected IAV infection at a postfusion step. This was confirmed by the lack of inhibition of IAV entry by proteasome inhibitors in a virus-like particle fusion assay.

scholarly journals Proteasome Inhibitors Reduce Thrombospondin-1 Release in Human Dysferlin-Deficient Myotubes

2019 ◽  
Author(s):  
Esther Fernández-Simón ◽  
Cinta Lleixà ◽  
Xavier Suarez-Calvet ◽  
Jordi Diaz-Manera ◽  
Isabel Illa ◽  
...  
Keyword(s):  
Vitamin D3 ◽  
Transmembrane Protein ◽  
Proteasome Inhibitors ◽  
Ubiquitin Proteasome System ◽  
Muscle Membrane ◽  
Enzyme Linked Immunosorbent Assay ◽  
Missense Mutations ◽  
Membrane Repair ◽  
Thrombospondin 1 ◽  
Ubiquitin Proteasome

Abstract Background: Dysferlin is a type-II transmembrane protein and the causative gene of dysferlinopathies, which are characterized by absence or marked reduction in dysferlin protein and muscle weakness. Dysferlin is implicated in vesicle fusion, trafficking, and membrane repair. The muscle biopsy of patients with dysferlinopathy is characterized by the presence of inflammatory infiltrates. Release of thrombospondin-1 (TSP-1) by dysferlin deficient muscle has been reported as a possible factor of the inflammation observed in the muscle of both human and mouse models of dysferlinopathy. It has also been reported that treatment with vitamin D3 enhances dysferlin expression. The ubiquitin-proteasome system recognizes and removes proteins that fail to fold or assemble properly and previous studies suggest that its inhibition could have a therapeutic implication in muscle dystrophies. Here we assessed whether inhibition of the ubiquitin proteasome system prevented degradation of dysferlin in immortalized myoblasts from a patient carrying two missense mutationsMethods: Dysferlin deficient myotubes were treated with EB1089, a vitamin D3 analog, oprozomib and ixazomib to assess proteasome inhibition. Western blot was performed to analyze the effect of the different treatments on the recovery of dysferlin and myogenin expression. TSP-1 was quantified using Enzyme Linked Immunosorbent Assay to analyze the effect of these drugs on its release.A membrane repair assay was designed to assess the ability of treated myotubes to recover after membrane injury. Data were analyzed using a one-way ANOVA test followed by by Tukey post hoc test and analysis of variance. Ap≤0.05 was considered statistically significant. Results : Treatment with proteasome inhibitors and EB1089 resulted in a slight increase of dysferlin expression which was accompanied by a low increase of myogenin expression. Also, EB1089 and proteasome inhibitors reduced the release of TSP-1 in myotubes from a dysferlinopathy patient. However, the increase of dysferlin had no effect on the repair of muscle membrane after injury. Conclusions: Our findings indicate that the ubiquitin-proteasome system might not be the main mechanism of mutant dysferlin degradation. However, its inhibition could help to improve muscle inflammation by reducing TSP-1 release.

scholarly journals Proteasome-associated ubiquitin ligase relays target plant hormone-specific transcriptional activators

2021 ◽  
Author(s):  
Zhishuo Wang ◽  
Beatriz Orosa-Puente ◽  
Mika Nomoto ◽  
Heather Grey ◽  
Thomas Potuschak ◽  
...  
Keyword(s):  
Ubiquitin Ligase ◽  
Stress Responses ◽  
Plant Hormone ◽  
Ubiquitin Ligases ◽  
Ubiquitin Proteasome System ◽  
Transcriptional Activators ◽  
Sequential Action ◽  
Ubiquitin Proteasome ◽  
Universal Mechanism ◽  
Target Plant

The ubiquitin-proteasome system is vital to hormone-mediated developmental and stress responses in plants. Ubiquitin ligases target hormone-specific transcriptional activators (TAs) for degradation, but how TAs are processed by proteasomes remains unknown. We report that in Arabidopsis the salicylic acid- and ethylene-responsive TAs, NPR1 and EIN3, are relayed from pathway-specific ubiquitin ligases to proteasome-associated HECT-type UPL3/4 ligases. Activity and stability of NPR1 was regulated by sequential action of three ubiquitin ligases, including UPL3/4, while proteasome processing of EIN3 required physical handover between ethylene-responsive SCFEBF2 and UPL3/4 ligases. Consequently, UPL3/4 controlled extensive hormone-induced developmental and stress-responsive transcriptional programmes. Thus, our findings identify unknown ubiquitin ligase relays that terminate with proteasome-associated HECT-type ligases, which may be a universal mechanism for processive degradation of proteasome-targeted TAs and other substrates.

scholarly journals Characterization of MORN2 stability and regulatory function in LC3-associated phagocytosis in macrophages

Biology Open ◽  
2020 ◽  
Vol 9 (6) ◽  
pp. bio051029 ◽  
Author(s):  
Maya Morita ◽  
Mayu Kajiye ◽  
Chiye Sakurai ◽  
Shuichi Kubo ◽  
Miki Takahashi ◽  
...  
Keyword(s):  
Membrane Trafficking ◽  
Ubiquitin Proteasome System ◽  
Snare Proteins ◽  
Regulatory Function ◽  
Limiting Factor ◽  
Sensitive Factor ◽  
Protein Receptors ◽  
Ubiquitin Proteasome ◽  
Syntaxin 11

ABSTRACTMicrotubule-associated protein A1/B1-light chain 3 (LC3)-associated phagocytosis (LAP) is a type of non-canonical autophagy that regulates phagosome maturation in macrophages. However, the role and regulatory mechanism of LAP remain largely unknown. Recently, the membrane occupation and recognition nexus repeat-containing-2 (MORN2) was identified as a key component of LAP for the efficient formation of LC3-recruiting phagosomes. To characterize MORN2 and elucidate its function in LAP, we established a MORN2-overexpressing macrophage line. At a steady state, MORN2 was partially cleaved by the ubiquitin-proteasome system. MORN2 overexpression promoted not only LC3-II production but also LAP phagosome (LAPosome) acidification during Escherichia coli uptake. Furthermore, the formation of LAPosomes containing the yeast cell wall component zymosan was enhanced in MORN2-overexpressing cells and depended on reactive oxygen species (ROS). Finally, MORN2-mediated LAP was regulated by plasma membrane-localized soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNAREs) such as SNAP-23 and syntaxin 11. Taken together, these findings demonstrate that MORN2, whose expression is downregulated via proteasomal digestion, is a limiting factor for LAP, and that membrane trafficking by SNARE proteins is involved in MORN2-mediated LAP.

Ubiquitin Proteasome System as a Potential Drug Target for Malaria

2018 ◽  
Vol 18 (5) ◽  
pp. 315-320 ◽  
Author(s):  
Pedro H. Scarpelli Pereira ◽  
Chiara Curra ◽  
Celia R.S. Garcia
Keyword(s):  
Proteasome Inhibitors ◽  
Ubiquitin Proteasome System ◽  
New Drugs ◽  
Complex Life Cycle ◽  
Mosquito Vector ◽  
Promising Alternative ◽  
Genes Encoding ◽  
Therapeutic Molecules ◽  
Ubiquitin Proteasome ◽  
Resistant Strains

Parasites of Plasmodium genus are responsible for causing malaria in humans. Resistant strains to all available antimalarials can be found in several locations around the globe, including parasites resistant to the latest generation of combination drugs, such as piperaquine + artemisinin. Plasmodium develops between two completely different hosts such as a vertebrate one and the mosquito vector, thus it has the ability to adapt to very extreme and different environments. Through the complex life cycle in the hosts, Plasmodium invades and replicates in totally different cells thus making the study of the biology of the parasite and the identification of targets for drug development affecting all stages very difficult. It was shown that host molecules, such as melatonin and derivatives, have a role in the progression and regulation of the parasite cell cycle; In fact, when the parasite is exposed to melatonin there is an increase in transcription levels of genes encoding for proteins related to the Ubiquitin Proteasome (UPS) System. This system is essential for the survival of the parasite, and drugs such as bortezomib, MLN-273, ZL3B, epoxomicins and salinosporamides are capable of eliminating the parasite by inhibiting the degradation of proteins via the proteasome system. In addition, the Plasmodium UPS shows low similarity to the ubiquitin proteasome system in Humans; the identification of unique targets to be used for therapeutic molecules development increases the importance of UPS studies in malaria challenging. Drugs that cause oxidative stress, such as artemisinin, show a strong synergistic effect with proteasome inhibitors, increasing the possibilities of combined therapies, which are more effective with lower concentration of drugs. Thus, the study of the mechanism of action of the UPS and the identification of potential targets for new drugs development are promising alternative strategies to fight the drug-resistance problem in malaria parasites.

Recent Advances in the Discovery of Novel Peptide Inhibitors Targeting 26S Proteasome

2019 ◽  
Vol 18 (12) ◽  
pp. 1656-1673
Author(s):  
Xinjie Gu ◽  
Shutao Ma
Keyword(s):  
Cancer Therapy ◽  
Proteasome Inhibitors ◽  
Ubiquitin Proteasome System ◽  
Peptide Inhibitors ◽  
26S Proteasome ◽  
Design Strategies ◽  
Intracellular Protein ◽  
Primary Tumors ◽  
Protein Levels ◽  
Ubiquitin Proteasome

Background: The 26S proteasome is a proteolytic complex of multimeric protease, which operates at the executive end of the Ubiquitin-Proteasome System (UPS) and degrades the polyubiquitylated proteins. Methods: After a brief introduction of 26S proteasome and Ubiquitin-Proteasome System (UPS), this review focuses on the structure and function of the 26S proteasome in intracellular protein level regulation. Then, physiological regulation mechanisms and processes are elaborated. In addition, the advantages and defects of approved 26S proteasome inhibitors were discussed. Finally, we summarized the novel peptide 26S proteasome inhibitors according to their structural classifications, highlighting their design strategies, inhibitory activity and Structure-Activity Relationships (SARs). Results: Cellular function maintenance relies on the proteasome metabolizing intracellular proteins to control intracellular protein levels, which is especially important for cancer cells to survive and proliferate. In primary tumors, proteasomes had a higher level and more potent activity. Currently, the approved small peptide inhibitors have proved their specific 26S proteasome inhibitory effects and considerable antitumor activities, but with obvious defects. Increasingly, novel peptide inhibitors are emerging and possess promising values in cancer therapy. Conclusion: Overall, the 26S proteasome is an efficient therapeutic target and novel 26S proteasome inhibitors hold potency for cancer therapy.

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