scholarly journals Ubiquitin-Specific Protease USP6 Regulates the Stability of the c-Jun Protein

2017 ◽  
Vol 38 (2) ◽  
Author(s):  
Lisheng Li ◽  
Hong Yang ◽  
Yan He ◽  
Ting Li ◽  
Jinan Feng ◽  
...  
Keyword(s):  
Cell Invasion ◽  
Deubiquitinating Enzyme ◽  
Cellular Functions ◽  
Expression Library ◽  
Downstream Signaling ◽  
Specific Protease ◽  
Ubiquitin Specific Protease ◽  
The Stability ◽  
Downstream Signaling Pathway ◽  
Dependent Mechanism

ABSTRACT The c- Jun gene encodes a transcription factor that has been implicated in many physiological and pathological processes. c-Jun is a highly unstable protein that is degraded through a ubiquitination/proteasome-dependent mechanism. However, the deubiquitinating enzyme (DUB) that regulates the stability of the c-Jun protein requires further investigation. Here, by screening a DUB expression library, we identified ubiquitin-specific protease 6 (USP6) and showed that it regulates the stability of the c-Jun protein in a manner depending on its enzyme activity. USP6 interacts with c-Jun and antagonizes its ubiquitination. USP6 overexpression upregulates the activity of the downstream signaling pathway mediated by c-Jun/AP-1 and promotes cell invasion. Moreover, many aberrant genes that are upregulated in USP6 translocated nodular fasciitis are great potential targets regulated by c-Jun. Based on our data, USP6 is an enzyme that deubiquitinates c-Jun and regulates its downstream cellular functions.

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 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 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.

An N-terminal SIAH-interacting motif regulates the stability of the ubiquitin specific protease (USP)-19

2013 ◽  
Vol 433 (4) ◽  
pp. 390-395 ◽  
Author(s):  
Kelly Velasco ◽  
Bin Zhao ◽  
Simone Callegari ◽  
Mikael Altun ◽  
Haiyin Liu ◽  
...  
Keyword(s):  
Specific Protease ◽  
Ubiquitin Specific Protease ◽  
The Stability

scholarly journals Ubiquitin-specific Protease 7 Is a Regulator of Ubiquitin-conjugating Enzyme UbE2E1

2013 ◽  
Vol 288 (23) ◽  
pp. 16975-16985 ◽  
Author(s):  
Feroz Sarkari ◽  
Keith Wheaton ◽  
Anthony La Delfa ◽  
Majda Mohamed ◽  
Faryal Shaikh ◽  
...  
Keyword(s):  
Dynamic Balance ◽  
Ubiquitin Proteasome System ◽  
Binding Motif ◽  
Deubiquitinating Enzyme ◽  
Interacting Protein ◽  
Identical Manner ◽  
Specific Protease ◽  
Ubiquitin Specific Protease

Ubiquitin-specific protease 7 (USP7) is a deubiquitinating enzyme found in all eukaryotes that catalyzes the removal of ubiquitin from specific target proteins. Here, we report that UbE2E1, an E2 ubiquitin conjugation enzyme with a unique N-terminal extension, is a novel USP7-interacting protein. USP7 forms a complex with UbE2E1 in vitro and in vivo through the ASTS USP7 binding motif within its N-terminal extension in an identical manner with other known USP7 binding proteins. We show that USP7 attenuates UbE2E1-mediated ubiquitination, an effect that requires the N-terminal ASTS sequence of UbE2E1 as well as the catalytic activity of USP7. Additionally, USP7 is critical in maintaining the steady state levels of UbE2E1 in cells. This study reveals a new cellular mechanism that couples the opposing activities of the ubiquitination machinery and a deubiquitinating enzyme to maintain and modulate the dynamic balance of the ubiquitin-proteasome system.

Sign in / Sign up

Export Citation Format

Share Document