The Ubiquitin C-Terminal Hydrolase L1 (UCH-L1) C Terminus Plays a Key Role in Protein Stability, but Its Farnesylation Is Not Required for Membrane Association in Primary Neurons

Bishop, Paul; Rubin, Philip; Thomson, Andrew; Rocca, Dan L.; Henley, Jeremy M.

doi:10.1074/jbc.m114.557124

Cited by 35 publications

(38 citation statements)

References 38 publications

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“…UCH-L1, as a deubiquitinating enzyme, which degrades misfolded proteins and recycles ubiquitin molecules under stress condition appears to play a key role in changes in protein profiles and neuroprotection in MDD. However, previous several studies demonstrate the function of UCH-L1 independently of its hydrolase activity ( 18 , 67 , 68 ), because its isoform UCH-L3 has much higher ubiquitin hydrolase activity than UCH-L1 inside cells ( 67 , 69 , 70 ). Both Cys90 and Cy152 of UCH-L1 are evolutionarily conserved in various species, but Cys152 appears only in UCH-L1, not in UCH-L3 ( 71 ), suggesting its specific role for UCH-L1 function.…”

Section: Discussionmentioning

confidence: 97%

Proteomic Analysis of Hippocampus in a Mouse Model of Depression Reveals Neuroprotective Function of Ubiquitin C-terminal Hydrolase L1 (UCH-L1) via Stress-induced Cysteine Oxidative Modifications

Choi¹,

Lee²,

Kang³

et al. 2018

Molecular & Cellular Proteomics

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Chronic physical restraint stress increases oxidative stress in the brain, and dysregulation of oxidative stress can be one of the causes of major depressive disorder. To understand the underlying mechanisms, we undertook a systematic proteomic analysis of hippocampus in a chronic restraint stress mouse model of depression. Combining two-dimensional gel electrophoresis (2D-PAGE) for protein separation with nanoUPLC-ESI-q-TOF tandem mass spectrometry, we identified sixty-three protein spots that changed in the hippocampus of mice subjected to chronic restraint stress. We identified and classified the proteins that changed after chronic stress, into three groups respectively functioning in neural plasticity, metabolic processes and protein aggregation. Of these, 5 proteins including ubiquitin C-terminal hydrolase L1 (UCH-L1), dihydropyrimidinase-related protein 2 (DPYL2), haloacid dehalogenase-like hydrolase domain-containing protein 2 (HDHD2), actin-related protein 2/3 complex subunit 5 (ARPC5) and peroxiredoxin-2 (PRDX2), showed pI shifts attributable to post-translational modifications. Further analysis indicated that UCH-L1 underwent differential oxidations of 2 cysteine residues following chronic stress. We investigated whether the oxidized form of UCH-L1 plays a role in stressed hippocampus, by comparing the effects of UCH-L1 and its Cys mutants on hippocampal cell line HT-22 in response to oxidative stress. This study demonstrated that UCH-L1 wild-type and cysteine to aspartic acid mutants, but not its cysteine to serine mutants, afforded neuroprotective effects against oxidative stress; there were no discernible differences between wild-type UCH-L1 and its mutants in the absence of oxidative stress. These findings suggest that cysteine oxidative modifications of UCH-L1 in the hippocampus play key roles in neuroprotection against oxidative stress caused in major depressive disorder.

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Section: Discussionmentioning

confidence: 97%

Proteomic Analysis of Hippocampus in a Mouse Model of Depression Reveals Neuroprotective Function of Ubiquitin C-terminal Hydrolase L1 (UCH-L1) via Stress-induced Cysteine Oxidative Modifications

Choi¹,

Lee²,

Kang³

et al. 2018

Molecular & Cellular Proteomics

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“…However, many other types of PTM are also known to be associated with various neurodegenerative conditions. These PTMs, not discussed in this review, include: adduct formation with DNA, lipids and proteins (de la Monte and Tong, 2014; Sultana et al, 2013), carbonylation (Ergin et al, 2013; Oikawa et al, 2014; Sultana et al, 2013), glycation (e.g., advanced glycation end products) (Byun et al, 2012; Choi et al, 2014), methylation (Pattaroni and Jacob, 2013; Peña-Altamira et al, 2013; Tradewell et al, 2012), N-linked glycosylation with Asn (Gonçalves et al, 2015; Mkhikian et al, 2011; Schedin-Weiss et al, 2014), O-linked glycosylation with Ser or Thr (Karababa et al, 2014; Lozano et al, 2014; Tan et al, 2014; Zhu et al, 2014), sumoylation (Gebriel et al, 2014; ; Nistico et al, 2014; Shahpasandzadeh et al, 2014), ubiquitination (Bishop et al, 2014; Gebriel et al, 2014; Karababa et al, 2014; Nistico et al, 2014; Schmid et al, 2013), etc.…”

Section: Consequences Of Increased Nitroxidative Stressmentioning

confidence: 99%

Mitochondrial dysfunction and cell death in neurodegenerative diseases through nitroxidative stress

et al. 2016

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Mitochondria are important for providing cellular energy ATP through the oxidative phosphorylation pathway. They are also critical in regulating many cellular functions including the fatty acid oxidation, the metabolism of glutamate and urea, the anti-oxidant defense, and the apoptosis pathway. Mitochondria are an important source of reactive oxygen species leaked from the electron transport chain while they are susceptible to oxidative damage, leading to mitochondrial dysfunction and tissue injury. In fact, impaired mitochondrial function is commonly observed in many types of neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, alcoholic dementia, brain ischemia-reperfusion related injury, and others, although many of these neurological disorders have unique etiological factors. Mitochondrial dysfunction under many pathological conditions is likely to be promoted by increased nitroxidative stress, which can stimulate post-translational modifications (PTMs) of mitochondrial proteins and/or oxidative damage to mitochondrial DNA and lipids. Furthermore, recent studies have demonstrated that various antioxidants, including naturally occurring flavonoids and polyphenols as well as synthetic compounds, can block the formation of reactive oxygen and/or nitrogen species, and thus ultimately prevent the PTMs of many proteins with improved disease conditions. Therefore, the present review is aimed to describe the recent research developments in the molecular mechanisms for mitochondrial dysfunction and tissue injury in neurodegenerative diseases and discuss translational research opportunities.

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“…Data revealed a separation by strain, with male and female C57BL/6 being similar, and mT/mG being most different from these ( Figure 5A). UCH-L1 (Ubiquitin C-terminal hydrolase L1, a major neuronal deubiquitinates of the degradative ubiquitin proteasome system (Bishop et al, 2014)) and…”

Section: Glomerular Endothelial Cells Exhibit Proteomic Differences Bmentioning

confidence: 99%

Tripartite separation of glomerular cell-types and proteomes from reporter-free mice

Hatje

Rinschen

Wedekind

et al. 2020

Preprint

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Purpose: The kidney glomerulus comprises a syncytium of podocytes, mesangial and endothelial cells, which jointly determine glomerular filtration barrier function, and thereby kidney and cardiovascular health. The understanding of this intricate functional unit and its intracellular communication beyond the transcriptome requires bulk isolation of these cell-types from glomeruli for subsequent biochemical investigations. Therefore, we developed a globally applicable tripartite isolation method for murine mesangial and endothelial cells and podocytes (timMEP). Methods: Glomerular cells were separated via a novel FACS-sort depending on a cell-specific antibody labeling in wildtype mice or based on a combination of transgenic fluorescent protein expression and antibody labeling in mT/mG mice. The purity of isolated cell-types was validated by qPCR and immunoblot. The proteome of podocytes, mesangial and endothelial cells was determined and compared between species, ages and gender of wildtype and mT/mG mice. The method was also applied to the podocyte-targeting immunologic injury model of THSD7A-associated membranous glomerulonephritis. Results: TimMEP enabled protein-biochemical analyses of podocytes, mesangial and endothelial cells derived from a single reporter free mouse. Proteomic analyses allowed the first characterization of podocyte, endothelial and mesangial proteomes of individual mice. Marker proteins for mesangial and endothelial proteins were determined, and protein-based interaction and intraglomerular cell communication networks were elucidated. Interestingly, analyses revealed significant cell-type specific proteome differences between mouse strains, artefacts induced by reporters, and alterations depending on gender and age. Within the glomerulus, timMEP resolved a fine-tuned initial stress response exclusively in podocytes after exposure to anti-THSD7A antibodies, which was not detectable using conventional analyses in whole glomeruli. Conclusion: Globally applicable timMEP abolishes the need for costly, time- and animal- consuming breeding of mice to glomerular cell-type reporters. TimMEP enables glomerular cell-type resolved investigations at the transcriptional and protein biochemical level in health and disease, while avoiding reporter-based artefacts, paving the way towards the comprehensive and systematic characterization of glomerular cell-type biology.

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The Ubiquitin C-Terminal Hydrolase L1 (UCH-L1) C Terminus Plays a Key Role in Protein Stability, but Its Farnesylation Is Not Required for Membrane Association in Primary Neurons

Cited by 35 publications

References 38 publications

Proteomic Analysis of Hippocampus in a Mouse Model of Depression Reveals Neuroprotective Function of Ubiquitin C-terminal Hydrolase L1 (UCH-L1) via Stress-induced Cysteine Oxidative Modifications

Proteomic Analysis of Hippocampus in a Mouse Model of Depression Reveals Neuroprotective Function of Ubiquitin C-terminal Hydrolase L1 (UCH-L1) via Stress-induced Cysteine Oxidative Modifications

Mitochondrial dysfunction and cell death in neurodegenerative diseases through nitroxidative stress

Tripartite separation of glomerular cell-types and proteomes from reporter-free mice

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