scholarly journals VCIP135 acts as a deubiquitinating enzyme during p97–p47-mediated reassembly of mitotic Golgi fragments

2004 ◽  
Vol 164 (7) ◽  
pp. 973-978 ◽  
Author(s):  
Yanzhuang Wang ◽  
Ayano Satoh ◽  
Graham Warren ◽  
Hemmo H. Meyer
Keyword(s):  
Membrane Fusion ◽  
Ubiquitin Proteasome System ◽  
Membrane Dynamics ◽  
Deubiquitinating Enzyme ◽  
Independent Function ◽  
Aaa Atpase ◽  
Ubiquitin Binding ◽  
Ubiquitin Binding Domain ◽  
Ubiquitin Proteasome ◽  
Cellular Pathways

The AAA-ATPase p97/Cdc48 functions in different cellular pathways using distinct sets of adapters and other cofactors. Together with its adaptor Ufd1–Npl4, it extracts ubiquitylated substrates from the membrane for subsequent delivery to the proteasome during ER-associated degradation. Together with its adaptor p47, on the other hand, it regulates several membrane fusion events, including reassembly of Golgi cisternae after mitosis. The finding of a ubiquitin-binding domain in p47 raises the question as to whether the ubiquitin–proteasome system is also involved in membrane fusion events. Here, we show that p97–p47-mediated reassembly of Golgi cisternae requires ubiquitin, but is not dependent on proteasome-mediated proteolysis. Instead, it requires the deubiquitinating activity of one of its cofactors, VCIP135, which reverses a ubiquitylation event that occurs during mitotic disassembly. Together, these data reveal a cycle of ubiquitylation and deubiquitination that regulates Golgi membrane dynamics during mitosis. Furthermore, they represent the first evidence for a proteasome-independent function of p97/Cdc48.

scholarly journals Ubiquitin, Autophagy and Neurodegenerative Diseases

Cells ◽  
2020 ◽  
Vol 9 (9) ◽  
pp. 2022 ◽  
Author(s):  
Yoshihisa Watanabe ◽  
Katsutoshi Taguchi ◽  
Masaki Tanaka
Keyword(s):  
Neurodegenerative Diseases ◽  
Ubiquitin Proteasome System ◽  
Binding Domain ◽  
Therapeutic Application ◽  
Selective Autophagy ◽  
Ubiquitin Binding ◽  
Selective Incorporation ◽  
Ubiquitin Binding Domain ◽  
Ubiquitin Proteasome ◽  
Autophagy Activity

Ubiquitin signals play various roles in proteolytic and non-proteolytic functions. Ubiquitin signals are recognized as targets of the ubiquitin–proteasome system and the autophagy–lysosome pathway. In autophagy, ubiquitin signals are required for selective incorporation of cargoes, such as proteins, organelles, and microbial invaders, into autophagosomes. Autophagy receptors possessing an LC3-binding domain and a ubiquitin binding domain are involved in this process. Autophagy activity can decline as a result of genetic variation, aging, or lifestyle, resulting in the onset of various neurodegenerative diseases. This review summarizes the selective autophagy of neurodegenerative disease-associated protein aggregates via autophagy receptors and discusses its therapeutic application for neurodegenerative diseases.

scholarly journals Selective Microautophagy of Proteasomes is Initiated by ESCRT-0 and Is Promoted by Proteasome Ubiquitylation

2021 ◽  
Author(s):  
Jianhui Li ◽  
Mark Hochstrasser
Keyword(s):  
Ubiquitin Ligase ◽  
Normal Growth ◽  
Ubiquitin Proteasome System ◽  
Growth Conditions ◽  
Endosomal Sorting ◽  
Glucose Depletion ◽  
Ubiquitin Binding ◽  
Ubiquitin Proteasome ◽  
Low Glucose ◽  
Amp Activated Protein Kinase

The proteasome is central to proteolysis by the ubiquitin-proteasome system under normal growth conditions but is itself degraded through macroautophagy under nutrient stress. A recently described AMPK (AMP-activated protein kinase)-regulated ESCRT (endosomal sorting complex required for transport)-dependent microautophagy pathway also regulates proteasome trafficking and degradation in low glucose conditions in yeast. Aberrant proteasomes are more prone to microautophagy, suggesting the ESCRT system fine-tunes proteasome quality control under low glucose stress. Here we uncover additional features of the selective microautophagy of proteasomes. Genetic or pharmacological induction of aberrant proteasomes is associated with increased mono- or oligo-ubiquitylation of proteasome components, which appear to be recognized by ESCRT-0. AMPK controls this pathway in part by regulating the trafficking of ESCRT-0 to the vacuole surface, which also leads to degradation of the Vps27 subunit of ESCRT-0. The Rsp5 ubiquitin ligase contributes to proteasome subunit ubiquitylation, and multiple ubiquitin-binding elements in Vps27 are involved in their recognition. We propose that ESCRT-0 at the vacuole surface recognizes ubiquitylated proteasomes and initiates their microautophagic elimination during glucose depletion.

scholarly journals Advances in Deubiquitinating Enzyme Inhibition and Applications in Cancer Therapeutics

Cancers ◽  
2020 ◽  
Vol 12 (6) ◽  
pp. 1579 ◽  
Author(s):  
Ainsley Mike Antao ◽  
Apoorvi Tyagi ◽  
Kye-Seong Kim ◽  
Suresh Ramakrishna
Keyword(s):  
Protein Interactions ◽  
Cancer Therapeutics ◽  
Ubiquitin Proteasome System ◽  
Deubiquitinating Enzyme ◽  
Protein Protein Interactions ◽  
Deubiquitinating Enzymes ◽  
Cellular Functions ◽  
E3 Ligases ◽  
Ubiquitin Proteasome ◽  
Target Cancer

Since the discovery of the ubiquitin proteasome system (UPS), the roles of ubiquitinating and deubiquitinating enzymes (DUBs) have been widely elucidated. The ubiquitination of proteins regulates many aspects of cellular functions such as protein degradation and localization, and also modifies protein-protein interactions. DUBs cleave the attached ubiquitin moieties from substrates and thereby reverse the process of ubiquitination. The dysregulation of these two paramount pathways has been implicated in numerous diseases, including cancer. Attempts are being made to identify inhibitors of ubiquitin E3 ligases and DUBs that potentially have clinical implications in cancer, making them an important target in the pharmaceutical industry. Therefore, studies in medicine are currently focused on the pharmacological disruption of DUB activity as a rationale to specifically target cancer-causing protein aberrations. Here, we briefly discuss the pathophysiological and physiological roles of DUBs in key cancer-related pathways. We also discuss the clinical applications of promising DUB inhibitors that may contribute to the development of DUBs as key therapeutic targets in the future.

scholarly journals USP14 Inhibition Regulates Tumorigenesis by Inducing Autophagy in Lung Cancer In Vitro

2019 ◽  
Vol 20 (21) ◽  
pp. 5300 ◽  
Author(s):  
Kyung Ho Han ◽  
Minseok Kwak ◽  
Tae Hyeong Lee ◽  
Min-soo Park ◽  
In-ho Jeong ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Ubiquitin Proteasome System ◽  
Migration And Invasion ◽  
Deubiquitinating Enzyme ◽  
Lung Tumorigenesis ◽  
Ubiquitin Chain ◽  
Specific Protease ◽  
Ubiquitin Proteasome ◽  
Autophagy Pathway

The ubiquitin–proteasome system is an essential regulator of several cellular pathways involving oncogenes. Deubiquitination negatively regulates target proteins or substrates linked to both hereditary and sporadic forms of cancer. The deubiquitinating enzyme ubiquitin-specific protease 14 (USP14) is associated with proteasomes where it trims the ubiquitin chain on the substrate. Here, we found that USP14 is highly expressed in patients with lung cancer. We also demonstrated that USP14 inhibitors (IU1-47 and siRNA-USP14) significantly decreased cell proliferation, migration, and invasion in lung cancer. Remarkably, we found that USP14 negatively regulates lung tumorigenesis not only through apoptosis but also through the autophagy pathway. Our findings suggest that USP14 plays a crucial role in lung tumorigenesis and that USP14 inhibitors are potent drugs in lung cancer treatment.

scholarly journals The AAA-ATPase p97 is essential for outer mitochondrial membrane protein turnover

2011 ◽  
Vol 22 (3) ◽  
pp. 291-300 ◽  
Author(s):  
Shan Xu ◽  
Guihong Peng ◽  
Yang Wang ◽  
Shengyun Fang ◽  
Mariusz Karbowski
Keyword(s):  
Mitochondrial Membrane ◽  
Ubiquitin Proteasome System ◽  
Proteasomal Degradation ◽  
Degradation Pathway ◽  
Outer Mitochondrial Membrane ◽  
Aaa Atpase ◽  
Associated Proteins ◽  
Ubiquitin Proteasome ◽  
Molecular Components

Recent studies have revealed a role for the ubiquitin/proteasome system in the regulation and turnover of outer mitochondrial membrane (OMM)-associated proteins. Although several molecular components required for this process have been identified, the mechanism of proteasome-dependent degradation of OMM-associated proteins is currently unclear. We show that an AAA-ATPase, p97, is required for the proteasomal degradation of Mcl1 and Mfn1, two unrelated OMM proteins with short half-lives. A number of biochemical assays, as well as imaging of changes in localization of photoactivable GFP-fused Mcl1, revealed that p97 regulates the retrotranslocation of Mcl1 from mitochondria to the cytosol, prior to, or concurrent with, proteasomal degradation. Mcl1 retrotranslocation from the OMM depends on the activity of the ATPase domain of p97. Furthermore, p97-mediated retrotranslocation of Mcl1 can be recapitulated in vitro, confirming a direct mitochondrial role for p97. Our results establish p97 as a novel and essential component of the OMM-associated protein degradation pathway.

scholarly journals The Role of the Selective Adaptor p62 and Ubiquitin-Like Proteins in Autophagy

2014 ◽  
Vol 2014 ◽  
pp. 1-11 ◽  
Author(s):  
Mónika Lippai ◽  
Péter Lőw
Keyword(s):  
Ubiquitin Proteasome System ◽  
Degradation Pathways ◽  
Intracellular Pathogens ◽  
Protein Conjugation ◽  
Cytosolic Proteins ◽  
Ubiquitin Binding ◽  
Ubiquitin Proteasome ◽  
Point Of Intersection

The ubiquitin-proteasome system and autophagy were long viewed as independent, parallel degradation systems with no point of intersection. By now we know that these degradation pathways share certain substrates and regulatory molecules and show coordinated and compensatory function. Two ubiquitin-like protein conjugation pathways were discovered that are required for autophagosome biogenesis: the Atg12-Atg5-Atg16 and Atg8 systems. Autophagy has been considered to be essentially a nonselective process, but it turned out to be at least partially selective. Selective substrates of autophagy include damaged mitochondria, intracellular pathogens, and even a subset of cytosolic proteins with the help of ubiquitin-binding autophagic adaptors, such as p62/SQSTM1, NBR1, NDP52, and Optineurin. These proteins selectively recognize autophagic cargo and mediate its engulfment into autophagosomes by binding to the small ubiquitin-like modifiers that belong to the Atg8/LC3 family.

scholarly journals The ubiquitin–proteasome system regulates membrane fusion of yeast vacuoles

2006 ◽  
Vol 26 (2) ◽  
pp. 275-287 ◽  
Author(s):  
Maurits F Kleijnen ◽  
Donald S Kirkpatrick ◽  
Steven P Gygi
Keyword(s):  
Membrane Fusion ◽  
Ubiquitin Proteasome System ◽  
Ubiquitin Proteasome

scholarly journals Cell cycle regulation of VCIP135 deubiquitinase activity and function in p97/p47-mediated Golgi reassembly

2015 ◽  
Vol 26 (12) ◽  
pp. 2242-2251 ◽  
Author(s):  
Xiaoyan Zhang ◽  
Yanzhuang Wang
Keyword(s):  
Cell Cycle ◽  
Membrane Fusion ◽  
Mammalian Cells ◽  
Membrane Dynamics ◽  
Deubiquitinating Enzyme ◽  
Golgi Membrane ◽  
Interacting Protein ◽  
Daughter Cells ◽  
And Function ◽  
Cycle Regulation

In mammalian cells, the inheritance of the Golgi apparatus into the daughter cells during each cycle of cell division is mediated by a disassembly and reassembly process, and this process is precisely controlled by phosphorylation and ubiquitination. VCIP135 (valosin-containing protein p97/p47 complex–interacting protein, p135), a deubiquitinating enzyme required for p97/p47-mediated postmitotic Golgi membrane fusion, is phosphorylated at multiple sites during mitosis. However, whether phosphorylation directly regulates VCIP135 deubiquitinase activity and Golgi membrane fusion in the cell cycle remains unknown. We show that, in early mitosis, phosphorylation of VCIP135 by Cdk1 at a single residue, S130, is sufficient to inactivate the enzyme and inhibit p97/p47-mediated Golgi membrane fusion. At the end of mitosis, VCIP135 S130 is dephosphorylated, which is accompanied by the recovery of its deubiquitinase activity and Golgi reassembly. Our results demonstrate that phosphorylation and ubiquitination are coordinated via VCIP135 to control Golgi membrane dynamics in the cell cycle.

scholarly journals The p97-UBXN1 complex regulates aggresome formation

2020 ◽  
Author(s):  
Sirisha Mukkavalli ◽  
Jacob Aaron Klickstein ◽  
Betty Ortiz ◽  
Peter Juo ◽  
Malavika Raman
Keyword(s):  
Protein Aggregation ◽  
Mammalian Cells ◽  
Proteasome Inhibition ◽  
Adaptor Proteins ◽  
Ubiquitin Proteasome System ◽  
Aaa Atpase ◽  
Evolutionarily Conserved ◽  
Ubiquitin Proteasome ◽  
Aggresome Formation

AbstractThe recognition and disposal of misfolded proteins are essential for the maintenance of cellular homeostasis. Perturbations in the pathways that promote degradation of aberrant proteins contribute to a variety of protein aggregation disorders broadly termed proteinopathies. It is presently unclear how diverse disease-relevant aggregates are recognized and processed for degradation. The p97 AAA-ATPase in combination with a host of adaptor proteins functions to identify ubiquitylated proteins and target them for degradation by the ubiquitin-proteasome system or through autophagy. Mutations in p97 cause multi-system proteinopathies; however, the precise defects underlying these disorders are unclear given the large number of pathways that rely on p97 function. Here, we systematically investigate the role of p97 and its adaptors in the process of formation of aggresomes which are membrane-less structures containing ubiquitylated proteins that arise upon proteasome inhibition. We demonstrate that p97 mediates both aggresome formation and clearance in proteasome-inhibited cells. We identify a novel and specific role for the p97 adaptor UBXN1 in the process of aggresome formation. UBXN1 is recruited to ubiquitin-positive aggresomes and UBXN1 knockout cells are unable to form a single aggresome, and instead display dispersed ubiquitin aggregates. Furthermore, loss of p97-UBXN1 results in the increase in Huntingtin polyQ aggregates both in mammalian cells as well as in a C.elegans model of Huntington’s Disease. Together our work identifies evolutionarily conserved roles for p97 and its adaptor UBXN1 in the disposal of protein aggregates.

scholarly journals USP47-Mediated Deubiquitination and Stabilization of TCEA3 Attenuates Pyroptosis and Apoptosis of Colorectal Cancer Cells Induced by Chemotherapeutic Doxorubicin

2021 ◽  
Vol 12 ◽  
Author(s):  
Xiaodan Hou ◽  
Jun Xia ◽  
Yuan Feng ◽  
Long Cui ◽  
Yili Yang ◽  
...  
Keyword(s):  
Ectopic Expression ◽  
Elongation Factor ◽  
Disease Free Survival ◽  
Ubiquitin Proteasome System ◽  
Deubiquitinating Enzyme ◽  
Deubiquitinating Enzymes ◽  
Cellular Processes ◽  
Colorectal Cancer Cells ◽  
Ubiquitin Proteasome ◽  
Resistance To Doxorubicin

The ubiquitin–proteasome system regulates a variety of cellular processes including growth, differentiation and apoptosis. While E1, E2, and E3 are responsible for the conjugation of ubiquitin to substrates, deubiquitinating enzymes (DUBs) reverse the process to remove ubiquitin and edit ubiquitin chains, which have profound effects on substrates’ degradation, localization, and activities. In the present study, we found that the deubiquitinating enzyme USP47 was markedly decreased in primary colorectal cancers (CRC). Its reduced expression was associated with shorter disease-free survival of CRC patients. In cultured CRC cells, knockdown of USP47 increased pyroptosis and apoptosis induced by chemotherapeutic doxorubicin. We found that USP47 was able to bind with transcription elongation factor a3 (TCEA3) and regulated its deubiquitination and intracellular level. While ectopic expression of USP47 increased cellular TCEA3 and resistance to doxorubicin, the effect was markedly attenuated by TCEA3 knockdown. Further analysis showed that the level of pro-apoptotic Bax was regulated by TCEA3. These results indicated that the USP47-TCEA3 axis modulates cell pyroptosis and apoptosis and may serve as a target for therapeutic intervention in CRC.

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