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 Interaction between Parkin and α-Synuclein in PARK2-Mediated Parkinson’s Disease

Cells ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 283
Author(s):  
Daniel Aghaie Madsen ◽  
Sissel Ida Schmidt ◽  
Morten Blaabjerg ◽  
Morten Meyer
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Ubiquitin Ligase ◽  
Current Knowledge ◽  
Lewy Bodies ◽  
Ubiquitin Proteasome System ◽  
Loss Of Function ◽  
Functional Interaction ◽  
Future Studies ◽  
Ubiquitin Proteasome

Parkin and α-synuclein are two key proteins involved in the pathophysiology of Parkinson’s disease (PD). Neurotoxic alterations of α-synuclein that lead to the formation of toxic oligomers and fibrils contribute to PD through synaptic dysfunction, mitochondrial impairment, defective endoplasmic reticulum and Golgi function, and nuclear dysfunction. In half of the cases, the recessively inherited early-onset PD is caused by loss of function mutations in the PARK2 gene that encodes the E3-ubiquitin ligase, parkin. Parkin is involved in the clearance of misfolded and aggregated proteins by the ubiquitin-proteasome system and regulates mitophagy and mitochondrial biogenesis. PARK2-related PD is generally thought not to be associated with Lewy body formation although it is a neuropathological hallmark of PD. In this review article, we provide an overview of post-mortem neuropathological examinations of PARK2 patients and present the current knowledge of a functional interaction between parkin and α-synuclein in the regulation of protein aggregates including Lewy bodies. Furthermore, we describe prevailing hypotheses about the formation of intracellular micro-aggregates (synuclein inclusions) that might be more likely than Lewy bodies to occur in PARK2-related PD. This information may inform future studies aiming to unveil primary signaling processes involved in PD and related neurodegenerative disorders.

scholarly journals Aggregation and Prion-Inducing Properties of the G-Protein Gamma Subunit Ste18 are Regulated by Membrane Association

2020 ◽  
Vol 21 (14) ◽  
pp. 5038
Author(s):  
Tatiana A. Chernova ◽  
Zhen Yang ◽  
Tatiana S. Karpova ◽  
John R. Shanks ◽  
Natalia Shcherbik ◽  
...  
Keyword(s):  
G Protein ◽  
De Novo ◽  
Ubiquitin Proteasome System ◽  
Membrane Association ◽  
Protein Assemblies ◽  
Gamma Subunit ◽  
Yeast Prions ◽  
Extracellular Stimuli ◽  
Ubiquitin Proteasome ◽  
And Control

Yeast prions and mnemons are respectively transmissible and non-transmissible self-perpetuating protein assemblies, frequently based on cross-β ordered detergent-resistant aggregates (amyloids). Prions cause devastating diseases in mammals and control heritable traits in yeast. It was shown that the de novo formation of the prion form [PSI+] of yeast release factor Sup35 is facilitated by aggregates of other proteins. Here we explore the mechanism of the promotion of [PSI+] formation by Ste18, an evolutionarily conserved gamma subunit of a G-protein coupled receptor, a key player in responses to extracellular stimuli. Ste18 forms detergent-resistant aggregates, some of which are colocalized with de novo generated Sup35 aggregates. Membrane association of Ste18 is required for both Ste18 aggregation and [PSI+] induction, while functional interactions involved in signal transduction are not essential for these processes. This emphasizes the significance of a specific location for the nucleation of protein aggregation. In contrast to typical prions, Ste18 aggregates do not show a pattern of heritability. Our finding that Ste18 levels are regulated by the ubiquitin-proteasome system, in conjunction with the previously reported increase in Ste18 levels upon the exposure to mating pheromone, suggests that the concentration-dependent Ste18 aggregation may mediate a mnemon-like response to physiological stimuli.

The ubiquitin proteasome system in atrophying skeletal muscle: roles and regulation

2016 ◽  
Vol 311 (3) ◽  
pp. C392-C403 ◽  
Author(s):  
Philippe A. Bilodeau ◽  
Erin S. Coyne ◽  
Simon S. Wing
Keyword(s):  
Signaling Pathways ◽  
Muscle Atrophy ◽  
Molecular Mechanisms ◽  
Muscle Wasting ◽  
Clinical Problem ◽  
Ubiquitin Proteasome System ◽  
Mechanisms Of Action ◽  
Loss Of Function ◽  
Critical Determinant ◽  
Ubiquitin Proteasome

Muscle atrophy complicates many diseases as well as aging, and its presence predicts both decreased quality of life and survival. Much work has been conducted to define the molecular mechanisms involved in maintaining protein homeostasis in muscle. To date, the ubiquitin proteasome system (UPS) has been shown to play an important role in mediating muscle wasting. In this review, we have collated the enzymes in the UPS whose roles in muscle wasting have been confirmed through loss-of-function studies. We have integrated information on their mechanisms of action to create a model of how they work together to produce muscle atrophy. These enzymes are involved in promoting myofibrillar disassembly and degradation, activation of autophagy, inhibition of myogenesis as well as in modulating the signaling pathways that control these processes. Many anabolic and catabolic signaling pathways are involved in regulating these UPS genes, but none appear to coordinately regulate a large number of these genes. A number of catabolic signaling pathways appear to instead function by inhibition of the insulin/IGF-I/protein kinase B anabolic pathway. This pathway is a critical determinant of muscle mass, since it can suppress key ubiquitin ligases and autophagy, activate protein synthesis, and promote myogenesis through its downstream mediators such as forkhead box O, mammalian target of rapamycin, and GSK3β, respectively. Although much progress has been made, a more complete inventory of the UPS genes involved in mediating muscle atrophy, their mechanisms of action, and their regulation will be useful for identifying novel therapeutic approaches to this important clinical problem.

scholarly journals The UNC-45 chaperone mediates sarcomere assembly through myosin degradation in Caenorhabditis elegans

2007 ◽  
Vol 177 (2) ◽  
pp. 205-210 ◽  
Author(s):  
Megan L. Landsverk ◽  
Shumin Li ◽  
Alex H. Hutagalung ◽  
Ayaz Najafov ◽  
Thorsten Hoppe ◽  
...  
Keyword(s):  
Caenorhabditis Elegans ◽  
Proteasome Inhibition ◽  
Thick Filament ◽  
Ubiquitin Proteasome System ◽  
Loss Of Function ◽  
Cellular Processes ◽  
Ubiquitin Proteasome ◽  
Myosin Motors ◽  
And Function ◽  
Sarcomere Assembly

Myosin motors are central to diverse cellular processes in eukaryotes. Homologues of the myosin chaperone UNC-45 have been implicated in the assembly and function of myosin-containing structures in organisms from fungi to humans. In muscle, the assembly of sarcomeric myosin is regulated to produce stable, uniform thick filaments. Loss-of-function mutations in Caenorhabditis elegans UNC-45 lead to decreased muscle myosin accumulation and defective thick filament assembly, resulting in paralyzed animals. We report that transgenic worms overexpressing UNC-45 also display defects in myosin assembly, with decreased myosin content and a mild paralysis phenotype. We find that the reduced myosin accumulation is the result of degradation through the ubiquitin/proteasome system. Partial proteasome inhibition is able to restore myosin protein and worm motility to nearly wild-type levels. These findings suggest a mechanism in which UNC-45–related proteins may contribute to the degradation of myosin in conditions such as heart failure and muscle wasting.

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 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 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.

Abstract 269: Duo-impairment of the Ubiquitin-Proteasome System and Autophagy by Ablation of COP9 Signalosome Subunit 8 Activates a Programmed Necrosis Pathway Mediated by RIP1-RIP3 Kinases but not Cyclophilin D-regulated Mitochondrial Membrane Permeability

2014 ◽  
Vol 115 (suppl_1) ◽  
Author(s):  
Changhua Wang ◽  
Andrea Jahn ◽  
Huabo Su ◽  
Xuejun Wang
Keyword(s):  
Membrane Permeability ◽  
Mitochondrial Membrane ◽  
Membrane Integrity ◽  
Premature Death ◽  
Ubiquitin Proteasome System ◽  
Cop9 Signalosome ◽  
Cyclophilin D ◽  
Mitochondrial Membrane Permeability ◽  
Programmed Necrosis ◽  
Ubiquitin Proteasome

Programmed cell death includes apoptosis and programmed necrosis (AKA, necroptosis). A well-recognized feature of necrosis is the loss of membrane integrity of the dying cell. Cells undergoing apoptosis, however, maintain their membrane integrity. We previously reported massive cardiomyocyte (CM) necrosis, before increased apoptosis is discernible, in mouse hearts with cardiomyocyte-restricted knockout of the COP9 signalosome subunit 8 (CR-Csn8KO). This is associated with defective autophagosome maturation and ubiquitin-proteasome system (UPS) dysfunction. Consequently, mice with perinatal CR-Csn8KO develop rapidly dilated cardiomyopathy (DCM) and die prematurely. The present study sought to search for the mechanisms underlying the CM necrosis. Here our immunoprecipitation revealed significant increases of RIP1-interacted RIP3 in CR-Csn8KO myocardium, indicative of activation of the RIP1-RIP3 pathway. The RIP1-RIP3 pathway is known to mediate necroptosis. To further test whether RIP1 activation plays an essential role in CM necrosis in CR-Csn8KO mice, we treated the mice with a RIP1 kinase specific inhibitor necrostatin-1 (Nec-1) or vehicle control via osmotic mini-pump implanted in the peritoneal cavity at 2 weeks of age. Nec-1 significantly suppressed CM necrosis as measured by the positivity of Evan’s blue dye (EBD) uptake (p<0.00001), prevented left ventricle dilatation (p<0.05) at 3 weeks, and delayed premature death of the CR-Csn8KO mice (p=0.0072). These results demonstrate that CM necrosis in CR-Csn8KO mice is necroptosis in which the RIP1-RIP3 kinases-mediated pathway plays a major pathogenic role, and that CM necroptosis is the primary cause of DCM and mouse premature death. Increased mitochondrial membrane permeability, which can be suppressed by inhibition of cyclophilin D, has been shown to play a critical mediating role in myocytes necrosis. Hence, we cross-bred CR-Csn8KO mice with cyclophilin D knockout mice and obtained the Kaplan-Meier survival curve. Unexpectedly, cyclophilin D deficiency exacerbated the premature death of CR-Csn8KO mice (p=0.007), indicating that cyclophilin D regulated mitochondrial membrane permeability does not play an important role in CM necrosis in CR-Csn8KO mouse hearts.

scholarly journals PARylation prevents the proteasomal degradation of topoisomerase I DNA-protein crosslinks and induces their deubiquitylation

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Yilun Sun ◽  
Jiji Chen ◽  
Shar-yin N. Huang ◽  
Yijun P. Su ◽  
Wenjie Wang ◽  
...  
Keyword(s):  
Single Molecule ◽  
Topoisomerase I ◽  
Ubiquitin Proteasome System ◽  
Live Cells ◽  
Ubiquitin Proteasome ◽  
Repair Factor ◽  
The Impact ◽  
Protein Crosslinks ◽  
Potential Regulatory Role

AbstractPoly(ADP)-ribosylation (PARylation) regulates chromatin structure and recruits DNA repair proteins. Using single-molecule fluorescence microscopy to track topoisomerase I (TOP1) in live cells, we found that sustained PARylation blocked the repair of TOP1 DNA-protein crosslinks (TOP1-DPCs) in a similar fashion as inhibition of the ubiquitin-proteasome system (UPS). PARylation of TOP1-DPC was readily revealed by inhibiting poly(ADP-ribose) glycohydrolase (PARG), indicating the otherwise transient and reversible PARylation of the DPCs. As the UPS is a key repair mechanism for TOP1-DPCs, we investigated the impact of TOP1-DPC PARylation on the proteasome and found that the proteasome is unable to associate with and digest PARylated TOP1-DPCs. In addition, PARylation recruits the deubiquitylating enzyme USP7 to reverse the ubiquitylation of PARylated TOP1-DPCs. Our work identifies PARG as repair factor for TOP1-DPCs by enabling the proteasomal digestion of TOP1-DPCs. It also suggests the potential regulatory role of PARylation for the repair of a broad range of DPCs.

scholarly journals Functional Characterisation of the Autophagy ATG12~5/16 Complex in Dictyostelium discoideum

Cells ◽  
2020 ◽  
Vol 9 (5) ◽  
pp. 1179 ◽  
Author(s):  
Malte Karow ◽  
Sarah Fischer ◽  
Susanne Meßling ◽  
Roman Konertz ◽  
Jana Riehl ◽  
...  
Keyword(s):  
Dictyostelium Discoideum ◽  
Ubiquitin Proteasome System ◽  
Strong Increase ◽  
Knock Out ◽  
E Coli ◽  
Atg Proteins ◽  
Functional Characterisation ◽  
Independent Functions ◽  
Ubiquitin Proteasome ◽  
Essential Function

Macroautophagy, a highly conserved and complex intracellular degradative pathway, involves more than 20 core autophagy (ATG) proteins, among them the hexameric ATG12~5/16 complex, which is part of the essential ubiquitin-like conjugation systems in autophagy. Dictyostelium discoideum atg5 single, atg5/12 double, and atg5/12/16 triple gene knock-out mutant strains displayed similar defects in the conjugation of ATG8 to phosphatidylethanolamine, development, and cell viability upon nitrogen starvation. This implies that ATG5, 12 and 16 act as a functional unit in canonical autophagy. Macropinocytosis of TRITC dextran and phagocytosis of yeast were significantly decreased in ATG5¯ and ATG5¯/12¯ and even further in ATG5¯/12¯/16¯ cells. In contrast, plaque growth on Klebsiella aerogenes was about twice as fast for ATG5¯ and ATG5¯/12¯/16¯ cells in comparison to AX2, but strongly decreased for ATG5¯/12¯ cells. Along this line, phagocytic uptake of Escherichia coli was significantly reduced in ATG5¯/12¯ cells, while no difference in uptake, but a strong increase in membrane association of E. coli, was seen for ATG5¯ and ATG5¯/12¯/16¯ cells. Proteasomal activity was also disturbed in a complex fashion, consistent with an inhibitory activity of ATG16 in the absence of ATG5 and/or ATG12. Our results confirm the essential function of the ATG12~5/16 complex in canonical autophagy, and furthermore are consistent with autophagy-independent functions of the complex and its individual components. They also strongly support the placement of autophagy upstream of the ubiquitin-proteasome system (UPS), as a fully functional UPS depends on autophagy.

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