scholarly journals Activation of the membrane-bound Nrf1 transcription factor by USP19, a tail-anchored ubiquitin-specific protease in the endoplasmic reticulum

2020 ◽  
Author(s):  
Shaofan Hu ◽  
Yuancai Xiang ◽  
Lu Qiu ◽  
Meng Wang ◽  
Yiguo Zhang
Keyword(s):  
Endoplasmic Reticulum ◽  
Transcription Factor ◽  
Glucose Deprivation ◽  
Deubiquitinating Enzyme ◽  
Specific Protease ◽  
Membrane Bound ◽  
Xenograft Mice ◽  
Ubiquitin Specific Protease ◽  
And Oxidative Stress ◽  
Modest Reduction

AbstractThe membrane-bound transcription factor Nrf1 (i.e., encoded by Nfe2l1) is activated by sensing glucose deprivation, cholesterol excess, proteasomal inhibition and oxidative stress, and then mediates distinct signaling responses in order to maintain cellular homeostasis. Here, we found that Nrf1 stability and transactivity are enhanced by USP19, a tail-anchored ubiquitin-specific protease in the endoplasmic reticulum (ER). Further experiments revealed that USP19 directly interacts with Nrf1 in proximity to the ER and acts as a deubiquitinating enzyme to remove ubiquitin moieties from this protein and hence circumvent potential proteasomal degradation. Such USP19-mediated effect takes place only after Nrf1 is retrotranslocated by p97 out of ER membranes. Conversely, knockout of USP19 causes significant decreases in Nrf1 abundance and its active isoform entering the nucleus, resulting in down-regulation of its target proteasomal subunits. This led to a modest reduction of USP19−/−-derived tumor growth in xenograft mice, when compared with wild-type controls. Altogether, these demonstrate that USP19 serves as a novel mechanistic modulator of Nrf1, but not Nrf2. In turn, our additional evidence has also unraveled that transcriptional expression of endogenous USP19 and its promoter-driven reporter genes is regulated by Nrf2, as well by Nrf1, at distinct layers within a complex hierarchical regulatory network.

scholarly journals Deubiquitinating Enzyme USP8 Is Essential for Skeletogenesis by Regulating Wnt Signaling

2021 ◽  
Vol 22 (19) ◽  
pp. 10289
Author(s):  
Sachin Chaugule ◽  
Jung-Min Kim ◽  
Yeon-Suk Yang ◽  
Klaus-Peter Knobeloch ◽  
Xi He ◽  
...  
Keyword(s):  
Stem Cells ◽  
Skeletal Development ◽  
Fine Tuning ◽  
Osteogenic Potential ◽  
Deubiquitinating Enzyme ◽  
Renal Capsule ◽  
Wild Type ◽  
Lysosomal Degradation ◽  
Specific Protease ◽  
Ubiquitin Specific Protease

Disturbance in a differentiation program of skeletal stem cells leads to indecorous skeletogenesis. Growing evidence suggests that a fine-tuning of ubiquitin-mediated protein degradation is crucial for skeletal stem cells to maintain their stemness and osteogenic potential. Here, we demonstrate that the deubiquitinating enzyme (DUB) ubiquitin-specific protease 8 (USP8) stabilizes the Wnt receptor frizzled 5 (FZD5) by preventing its lysosomal degradation. This pathway is essential for Wnt/β-catenin signaling and the differentiation of osteoprogenitors to mature osteoblasts. Accordingly, deletion of USP8 in osteoprogenitors (Usp8Osx) resulted in a near-complete blockade in skeletal mineralization, similar to that seen in mice with defective Wnt/β-catenin signaling. Likewise, transplanting USP8-deficient osteoprogenitors under the renal capsule in wild-type secondary hosts did not to induce bone formation. Collectively, this study unveils an essential role for the DUB USP8 in Wnt/β-catenin signaling in osteoprogenitors and osteogenesis during skeletal development.

scholarly journals Ubiquitin-Specific Protease 25 Functions in Endoplasmic Reticulum-Associated Degradation

PLoS ONE ◽  
2012 ◽  
Vol 7 (5) ◽  
pp. e36542 ◽  
Author(s):  
Jessica R. Blount ◽  
Aaron A. Burr ◽  
Amanda Denuc ◽  
Gemma Marfany ◽  
Sokol V. Todi
Keyword(s):  
Endoplasmic Reticulum ◽  
Endoplasmic Reticulum Associated Degradation ◽  
Specific Protease ◽  
Ubiquitin Specific Protease

scholarly journals The ubiquitin-specific protease USP8 deubiquitinates and stabilizes Cx43

2018 ◽  
Vol 293 (21) ◽  
pp. 8275-8284 ◽  
Author(s):  
Jian Sun ◽  
Qianwen Hu ◽  
Hong Peng ◽  
Cheng Peng ◽  
Liheng Zhou ◽  
...  
Keyword(s):  
Connexin 43 ◽  
Cultured Cells ◽  
Deubiquitinating Enzyme ◽  
Human Breast ◽  
Dye Transfer ◽  
Protein Levels ◽  
Mammalian Tissues ◽  
Specific Protease ◽  
Bona Fide ◽  
Ubiquitin Specific Protease

Connexin-43 (Cx43, also known as GJA1) is the most ubiquitously expressed connexin isoform in mammalian tissues. It forms intercellular gap junction (GJ) channels, enabling adjacent cells to communicate both electrically and metabolically. Cx43 is a short-lived protein which can be quickly degraded by the ubiquitin-dependent proteasomal, endolysosomal, and autophagosomal pathways. Here, we report that the ubiquitin-specific peptidase 8 (USP8) interacts with and deubiquitinates Cx43. USP8 reduces both multiple monoubiquitination and polyubiquitination of Cx43 to prevent autophagy-mediated degradation. Consistently, knockdown of USP8 results in decreased Cx43 protein levels in cultured cells and suppresses intercellular communication, revealed by the dye transfer assay. In human breast cancer specimens, the expression levels of USP8 and Cx43 proteins are positively correlated. Taken together, these results identified USP8 as a crucial and bona fide deubiquitinating enzyme involved in autophagy-mediated degradation of Cx43.

scholarly journals Does inactivation of USP14 enhance degradation of proteasomal substrates that are associated with neurodegenerative diseases?

F1000Research ◽  
2016 ◽  
Vol 5 ◽  
pp. 137 ◽  
Author(s):  
Daniel Ortuno ◽  
Holly J. Carlisle ◽  
Silke Miller
Keyword(s):  
Neurodegenerative Diseases ◽  
Published Data ◽  
Deubiquitinating Enzyme ◽  
Polyubiquitin Chain ◽  
Cellular Models ◽  
Endogenous Expression ◽  
Age Related ◽  
Specific Protease ◽  
Ubiquitin Specific Protease ◽  
Control Protein

A common pathological hallmark of age-related neurodegenerative diseases is the intracellular accumulation of protein aggregates such as α-synuclein in Parkinson’s disease, TDP-43 in ALS, and tau in Alzheimer’s disease. Enhancing intracellular clearance of aggregation-prone proteins is a plausible strategy for slowing progression of neurodegenerative diseases and there is great interest in identifying molecular targets that control protein turnover. One of the main routes for protein degradation is through the proteasome, a multisubunit protease that degrades proteins that have been tagged with a polyubiquitin chain by ubiquitin activating and conjugating enzymes. Published data from cellular models indicate that Ubiquitin-specific protease 14 (USP14), a deubiquitinating enzyme (DUB), slows the degradation of tau and TDP-43 by the proteasome and that an inhibitor of USP14 increases the degradation of these substrates. We conducted similar experiments designed to evaluate tau, TDP-43, or α-synuclein levels in cells after overexpressing USP14 or knocking down endogenous expression by siRNA.

scholarly journals USP19 is a ubiquitin-specific protease regulated in rat skeletal muscle during catabolic states

2005 ◽  
Vol 288 (4) ◽  
pp. E693-E700 ◽  
Author(s):  
Lydie Combaret ◽  
Olasunkanmi A. J. Adegoke ◽  
Nathalie Bedard ◽  
Vickie Baracos ◽  
Didier Attaix ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Muscle Mass ◽  
De Novo ◽  
Deubiquitinating Enzyme ◽  
Mrna Levels ◽  
Deubiquitinating Enzymes ◽  
Rat Skeletal Muscle ◽  
Ubiquitin System ◽  
Specific Protease ◽  
Ubiquitin Specific Protease

Ubiquitin-dependent proteolysis is activated in skeletal muscle atrophying in response to various catabolic stimuli. Previous studies have demonstrated activation of ubiquitin conjugation. Because ubiquitination can also be regulated by deubiquitinating enzymes, we used degenerate oligonucleotides derived from conserved sequences in the ubiquitin-specific protease (UBP) family of deubiquitinating enzymes in RT-PCR with skeletal muscle RNA to amplify putative deubiquitinating enzymes. We identified USP19, a 150-kDa deubiquitinating enzyme that is widely expressed in various tissues including skeletal muscle. Expression of USP19 mRNA increased by ∼30–200% in rat skeletal muscle atrophying in response to fasting, streptozotocin-induced diabetes, dexamethasone treatment, and cancer. Increased mRNA levels during fasting returned to normal with refeeding, but 1 day later than the normalization of rates of proteolysis and coincided instead with recovery of muscle mass. Indeed, in all catabolic treatments, USP19 mRNA was inversely correlated with muscle mass and provided an index of muscle mass that may be useful in many pathological conditions, using small human muscle biopsies. The increased expression of this deubiquitinating enzyme under conditions of increased proteolysis suggests that it may play a role in regeneration of free ubiquitin either coincident with or after proteasome-mediated degradation of substrates. USP19 may also be involved in posttranslational processing of polyubiquitin produced de novo in response to induction of the polyubiquitin genes seen under these conditions. Deubiquitinating enzymes thus appear involved in muscle wasting and implicate a widening web of regulation of genes in the ubiquitin system in this process.

scholarly journals Activation of Transcription Factor Nrf-2 and Its Downstream Targets in Response to Moloney Murine Leukemia Virus ts1-Induced Thiol Depletion and Oxidative Stress in Astrocytes

2004 ◽  
Vol 78 (21) ◽  
pp. 11926-11938 ◽  
Author(s):  
Wenan Qiang ◽  
Jodi M. Cahill ◽  
Jinrong Liu ◽  
Xianghong Kuang ◽  
Na Liu ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Endoplasmic Reticulum ◽  
Cell Death ◽  
Transcription Factor ◽  
Murine Leukemia Virus ◽  
Leukemia Virus ◽  
Moloney Murine Leukemia Virus ◽  
Ros Accumulation ◽  
And Oxidative Stress ◽  
Murine Leukemia

ABSTRACT The neuroimmunodegenerative syndrome that develops in mice infected with ts1, a mutant of Moloney murine leukemia virus, resembles human AIDS. Both ts1 and human immunodeficiency virus type 1 infect astrocytes, microglia, and oligodendrocytes but do not infect neurons. Oxidative stress has been implicated in the neuropathology of AIDS dementia and other neurodegenerative diseases. We report here that ts1 infection of astrocytes (both transformed C1 cells and primary cultures) also induces thiol (i.e., glutathione and cysteine) depletion and reactive oxygen species (ROS) accumulation, events occurring in parallel with viral envelope precursor gPr80 env accumulation and upregulated expression of endoplasmic reticulum chaperones GRP78 and GRP94. Furthermore, ts1-infected astrocytes mobilize their thiol redox defenses by upregulating levels of the Nrf-2 transcription factor, as well its targets, the xCT cystine/glutamate antiporter, γ-glutamylcysteine ligase, and glutathione peroxidase. Depleting intracellular thiols by treating uninfected astrocytes with buthionine sulfoximine (BSO), a glutathione synthesis inhibitor, or by culturing in cystine-deficient medium, also induces ROS accumulation, activates Nrf-2, and upregulates Nrf-2 target gene expression in these astrocytes. Overexpression of Nrf-2 in astrocytes specifically increases expression of the above thiol synthesis-related proteins. Further treatment with BSO or N-acetylcysteine in transfected cells modulates this expression. Thiol depletion also accelerates cell death, while thiol supplementation promotes survival of ts1-infected cells. Together, our results indicate that ts1 infection of astrocytes, along with ts1-induced gPr80 env accumulation, endoplasmic reticulum stress, thiol depletion, and oxidative stress, accelerates cell death; in response to the thiol depletion and oxidative stress, astrocytes activate their Nrf-2-mediated thiol antioxidant defenses, promoting cell survival.

scholarly journals Ceapins inhibit ATF6α signaling by selectively preventing transport of ATF6α to the Golgi apparatus during ER stress

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Ciara M Gallagher ◽  
Peter Walter
Keyword(s):  
Endoplasmic Reticulum ◽  
Transcription Factor ◽  
Protein Folding ◽  
Golgi Apparatus ◽  
Er Stress ◽  
Target Genes ◽  
Spatial Separation ◽  
Oligomeric State ◽  
Er Exit Sites ◽  
Membrane Bound

The membrane-bound transcription factor ATF6α is activated by proteolysis during endoplasmic reticulum (ER) stress. ATF6α target genes encode foldases, chaperones, and lipid biosynthesis enzymes that increase protein-folding capacity in response to demand. The off-state of ATF6α is maintained by its spatial separation in the ER from Golgi-resident proteases that activate it. ER stress induces trafficking of ATF6α. We discovered Ceapins, a class of pyrazole amides, as selective inhibitors of ATF6α signaling that do not inhibit the Golgi proteases or other UPR branches. We show that Ceapins block ATF6α signaling by trapping it in ER-resident foci that are excluded from ER exit sites. Removing the requirement for trafficking by pharmacological elimination of the spatial separation of the ER and Golgi apparatus restored cleavage of ATF6α in the presence of Ceapins. Washout of Ceapins resensitized ATF6α to ER stress. These results suggest that trafficking of ATF6α is regulated by its oligomeric state.

scholarly journals Cleavage of the membrane-bound transcription factor OASIS in response to endoplasmic reticulum stress

2006 ◽  
Vol 96 (4) ◽  
pp. 1090-1100 ◽  
Author(s):  
Tomohiko Murakami ◽  
Shinichi Kondo ◽  
Maiko Ogata ◽  
Soshi Kanemoto ◽  
Atsushi Saito ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Transcription Factor ◽  
Endoplasmic Reticulum Stress ◽  
Membrane Bound
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