scholarly journals Mitochondrial proteolytic stress induced by loss of mortalin function is rescued by Parkin and PINK1

2014 ◽  
Vol 5 (4) ◽  
pp. e1180-e1180 ◽  
Author(s):  
L F Burbulla ◽  
J C Fitzgerald ◽  
K Stegen ◽  
J Westermeier ◽  
A-K Thost ◽  
...  
Keyword(s):  
Proteolytic Stress

scholarly journals Adaptability of the ubiquitin-proteasome system to proteolytic and folding stressors

2020 ◽  
Vol 220 (3) ◽  
Author(s):  
Jeremy J. Work ◽  
Onn Brandman
Keyword(s):  
Ubiquitin Proteasome System ◽  
Environmental Stressors ◽  
Quantitative Measurements ◽  
Substrate Degradation ◽  
Degradation Rates ◽  
Ubiquitin Proteasome ◽  
Substrate Stability ◽  
Quantitative Understanding ◽  
Proteolytic Stress ◽  
Stress Dependent

Aging, disease, and environmental stressors are associated with failures in the ubiquitin-proteasome system (UPS), yet a quantitative understanding of how stressors affect the proteome and how the UPS responds is lacking. Here we assessed UPS performance and adaptability in yeast under stressors using quantitative measurements of misfolded substrate stability and stress-dependent UPS regulation by the transcription factor Rpn4. We found that impairing degradation rates (proteolytic stress) and generating misfolded proteins (folding stress) elicited distinct effects on the proteome and on UPS adaptation. Folding stressors stabilized proteins via aggregation rather than overburdening the proteasome, as occurred under proteolytic stress. Still, the UPS productively adapted to both stressors using separate mechanisms: proteolytic stressors caused Rpn4 stabilization while folding stressors increased RPN4 transcription. In some cases, adaptation completely prevented loss of UPS substrate degradation. Our work reveals the distinct effects of proteotoxic stressors and the versatility of cells in adapting the UPS.

scholarly journals Quantitative analysis of the ubiquitin-proteasome system under proteolytic and folding stressors

2019 ◽  
Author(s):  
Jeremy J. Work ◽  
Onn Brandman
Keyword(s):  
Ubiquitin Proteasome System ◽  
Environmental Stressors ◽  
Quantitative Measurements ◽  
Substrate Degradation ◽  
Degradation Rates ◽  
Ubiquitin Proteasome ◽  
Substrate Stability ◽  
Quantitative Understanding ◽  
Proteolytic Stress ◽  
Stress Dependent

AbstractAging, disease, and environmental stressors are associated with failures in the ubiquitin-proteasome system (UPS), yet a quantitative understanding of how stressors affect the proteome and how the UPS responds is lacking. Here we assessed UPS performance and adaptability in yeast under stressors using quantitative measurements of misfolded substrate stability and stress-dependent UPS regulation by the transcription factor Rpn4. We found that impairing degradation rates (proteolytic stress) and generating misfolded proteins (folding stress) elicited distinct effects on the proteome and on UPS adaptation. Folding stressors stabilized proteins via aggregation rather than overburdening the proteasome, as occurred under proteolytic stress. Still, the UPS productively adapted to both stressors using separate mechanisms: proteolytic stressors caused Rpn4 stabilization while folding stressors increased RPN4 transcription. In some cases, adaptation completely prevented loss of UPS substrate degradation. Our work reveals the distinct effects of proteotoxic stressors and the versatility of cells in adapting the UPS.

scholarly journals Biology of Parkinson's disease: pathogenesis and pathophysiology of a multisystem neurodegenerative disorder

2004 ◽  
Vol 6 (3) ◽  
pp. 259-280 ◽  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Neurodegenerative Disorder ◽  
Experimental Studies ◽  
Symptomatic Treatment ◽  
Motor Dysfunction ◽  
Motor Impairments ◽  
Neurodegenerative Process ◽  
Midbrain Dopamine ◽  
Proteolytic Stress

Parkinson's disease (PD) is the second most common movement disorder. The characteristic motor impairments - bradykinesia, rigidity, and resting tremor - result from degenerative loss of midbrain dopamine (DA) neurons in the substantia nigra, and are responsive to symptomatic treatment with dopaminergic medications and functional neurosurgery. PD is also the second most common neurodegenerative disorder. Viewed from this perspective, PD is a disorder of multiple functional systems, not simply the motor system, and of multiple neurotransmitter systems, not merely that of DA. The characteristic pathology - intraneuronal Lewy body inclusions and reduced numbers of surviving neurons - is similar in each of the targeted neuron groups, suggesting a common neurodegenerative process. Pathological and experimental studies indicate that oxidative stress, proteolytic stress, and inflammation figure prominently in the pathogenesis of PD. Yet, whether any of these mechanisms plays a causal role in human PD is unknown, because to date we have no proven neuroprotective therapies that slow or reverse disease progression in patients with PD. We are beginning to understand the pathophysiology of motor dysfunction in PD, but its etiopathogenesis as a neurodegenerative disorder remains poorly understood.

scholarly journals Marcks Marks Resistance to Proteasome Inhibitors: Exocytosis of Polyubiquitinated Proteins in Bortezomib-Resistant Leukemia Cells

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3712-3712
Author(s):  
Niels Franke ◽  
Gertjan J.L. Kaspers ◽  
Yehuda G Assaraf ◽  
Johan Van Meerloo ◽  
Denise Niewerth ◽  
...  
Keyword(s):  
Acute Leukemia ◽  
Board Of Directors ◽  
Research Funding ◽  
Acquired Resistance ◽  
Proteasome Inhibitors ◽  
Leukemia Cells ◽  
Advisory Committees ◽  
Resistance Level ◽  
Proteolytic Stress ◽  
Resistant Cells

Abstract Despite the proven efficacy of proteasome inhibitors like bortezomib (BTZ) in multiple myeloma, mantle cell lymphoma, and in an experimental setting in pediatric acute leukemia, development of drug resistance remains a primary hindrance. To further understand the molecular basis underlying this chemoresistance phenomenon, various leukemia cell line models with acquired resistance to BTZ were developed and characterized. One common characteristic was that acquisition of point mutations in PSMB5 and upregulation of the β5-subunit of the proteasome were key determinants of BTZ-resistance in vitro. However, it remains unclear how these drug resistance modalities translate to the overcoming of proteolytic stress imposed by proteasome inhibition. From this perspective, we here undertook a multi-modality (DNA, mRNA, miRNA) array-based analyses of human CCRF-CEM acute leukemia cells and two BTZ-resistant subclones [one with a low resistance level [(10-fold, CEM/BTZ7) and another subline with a high resistance level (140-fold, CEM/BTZ200)] to determine whether or not complementary mechanisms contribute to BTZ resistance. Gene expression profiling studies revealed markedly reduced proteolytic stress induction in drug resistant cells over a broad BTZ concentration range. Moreover, several genes involved in cytoskeleton regulation and vesicle migration were increased in resistant cells. Of all genes, myristoylated alanine-rich C-kinase substrate (MARCKS) was the most differentially overexpressed gene with 25- to 42-fold upregulation in CEM/BTZ7 and CEM/BTZ200 cells, respectively. These observations were corroborated at the protein level and solely included unphosphorylated MARCKS rather than phosphorylated MARCKS, which was marginally expressed in CEM/BTZ cells. Interestingly, MARCKS upregulation was also observed in other BTZ-resistant and leukemia cells (CEM and THP1) with acquired resistance to the proteasome inhibitor salinosporamide A and the immunoproteasome inhibitor PR924. Given the overexpression of MARCKS in proteasome inhibitor-resistant leukemia cells, we further explored whether or not MARCKS overexpression may serve as a predictive marker of BTZ resistance in clinical samples of acute leukemia patients. To this end, we examined primary patient specimens from a phase II childhood refractory/relapsed ALL trial in which BTZ is administered in two intensive re-induction regimens containing vincristine, prednisone, PEG-asparaginase, doxorubicin or cyclophosphamide and etoposide followed by methotrexate treatment. MARCKS expression was demonstrated in 64% of therapy-refractory pediatric leukemia specimens (n=44) wherein higher MARCKS expression trended (p=0.09) towards a dismal response to BTZ-containing chemotherapy. Finally, from a mechanistic perspective, we showed a concentration-dependent association of MARCKS protein with the emergence of ubiquitin-containing vesicles in the resistant cells. This association with MARCKS protein was lost upon exocytosis of these vesicles, which were found to be extruded and taken up in co-cultures with recipient HeLa cells. Collectively, we propose a role for MARCKS in a novel mechanism of BTZ resistance through vesicular exocytosis of ubiquitinated proteins in BTZ-resistant cells to overcome proteolytic stress over a broad range of cytotoxic BTZ concentrations. Disclosures Kaspers: Janssen-Cilag: Research Funding. Smeets:Novartis: Employment. Zweegman:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding. Cloos:Takeda: Honoraria.

Oxidative and Proteolytic Stress in Homocysteine-Associated Cardiovascular Diseases

2010 ◽  
pp. 139-148
Author(s):  
Karni S. Moshal ◽  
Munish Kumar ◽  
Neetu Tyagi ◽  
Paras Kumar Mishra ◽  
Saumi Kundu ◽  
...  
Keyword(s):  
Cardiovascular Diseases ◽  
Proteolytic Stress

scholarly journals Branched ubiquitin chain binding and deubiquitination by UCH37 facilitate proteasome clearance of stress-induced inclusions

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Aixin Song ◽  
Zachary Hazlett ◽  
Dulith Abeykoon ◽  
Jeremy Dortch ◽  
Andrew Dillon ◽  
...  
Keyword(s):  
Active Site ◽  
Human Cells ◽  
26S Proteasome ◽  
Deubiquitinating Enzyme ◽  
Ubiquitin Chain ◽  
Proteasome Degradation ◽  
Chain Architecture ◽  
Cultured Human Cells ◽  
Branched Chain ◽  
Proteolytic Stress

UCH37, also known as UCHL5, is a highly conserved deubiquitinating enzyme (DUB) that associates with the 26S proteasome. Recently it was reported that UCH37 activity is stimulated by branched ubiquitin chain architectures. To understand how UCH37 achieves its unique debranching specificity, we performed biochemical and NMR structural analyses and found that UCH37 is activated by contacts with the hydrophobic patches of both distal ubiquitins that emanate from a branched ubiquitin. In addition, RPN13, which recruits UCH37 to the proteasome, further enhances branched-chain specificity by restricting linear ubiquitin chains from having access to the UCH37 active site. In cultured human cells under conditions of proteolytic stress, we show that substrate clearance by the proteasome is promoted by both binding and deubiquitination of branched polyubiquitin by UCH37. Proteasomes containing UCH37(C88A), which is catalytically inactive, aberrantly retain polyubiquitinated species as well as the RAD23B substrate shuttle factor, suggesting a defect in recycling of the proteasome. These findings provide a foundation to understand how proteasome degradation of substrates modified by a unique ubiquitin chain architecture is aided by a DUB.

scholarly journals Slender and stumpy bloodstream forms of Trypanosoma brucei display a differential response to extracellular acidic and proteolytic stress

2000 ◽  
Vol 267 (1) ◽  
pp. 18-27 ◽  
Author(s):  
Derek P Nolan ◽  
Sylvie Rolin ◽  
Jesus R. Rodriguez ◽  
Jan Van Den Abbeele ◽  
Etienne Pays
Keyword(s):  
Trypanosoma Brucei ◽  
Differential Response ◽  
Proteolytic Stress
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