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 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 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 Interplay between the Ubiquitin Proteasome System and Ubiquitin-Mediated Autophagy in Plants

Cells ◽  
2020 ◽  
Vol 9 (10) ◽  
pp. 2219 ◽  
Author(s):  
Tong Su ◽  
Mingyue Yang ◽  
Pingping Wang ◽  
Yanxiu Zhao ◽  
Changle Ma
Keyword(s):  
Common Factor ◽  
Ubiquitin Proteasome System ◽  
26S Proteasome ◽  
Regulatory Proteins ◽  
Selective Autophagy ◽  
Ubiquitin Proteasome ◽  
Conjugating Enzymes ◽  
Ubiquitin Conjugating Enzymes ◽  
Cellular Components ◽  
Protein Ligases

All eukaryotes rely on the ubiquitin-proteasome system (UPS) and autophagy to control the abundance of key regulatory proteins and maintain a healthy intracellular environment. In the UPS, damaged or superfluous proteins are ubiquitinated and degraded in the proteasome, mediated by three types of ubiquitin enzymes: E1s (ubiquitin activating enzymes), E2s (ubiquitin conjugating enzymes), and E3s (ubiquitin protein ligases). Conversely, in autophagy, a vesicular autophagosome is formed that transfers damaged proteins and organelles to the vacuole, mediated by a series of ATGs (autophagy related genes). Despite the use of two completely different componential systems, the UPS and autophagy are closely interconnected and mutually regulated. During autophagy, ATG8 proteins, which are autophagosome markers, decorate the autophagosome membrane similarly to ubiquitination of damaged proteins. Ubiquitin is also involved in many selective autophagy processes and is thus a common factor of the UPS and autophagy. Additionally, the components of the UPS, such as the 26S proteasome, can be degraded via autophagy, and conversely, ATGs can be degraded by the UPS, indicating cross regulation between the two pathways. The UPS and autophagy cooperate and jointly regulate homeostasis of cellular components during plant development and stress response.

scholarly journals The ubiquitin proteasome system in synaptic and axonal degeneration

2004 ◽  
Vol 165 (1) ◽  
pp. 27-30 ◽  
Author(s):  
Laura Korhonen ◽  
Dan Lindholm
Keyword(s):  
Neurodegenerative Diseases ◽  
Neurodegenerative Disorders ◽  
Drug Targets ◽  
Axonal Degeneration ◽  
Fruit Fly ◽  
Ubiquitin Proteasome System ◽  
Synaptic Protein ◽  
Ubiquitin Proteasome ◽  
Novel Drug ◽  
Novel Drug Targets

The ubiquitin proteasome system (UPS) contributes to the pathophysiology of neurodegenerative diseases, and it is also a major determinant of synaptic protein degradation and activity. Recent studies in rodents and in the fruit fly Drosophila have shown that the activity of the UPS is involved in axonal degeneration. Increased knowledge of the UPS in synaptic and axonal reactions may provide novel drug targets for treatments of neuronal injuries and neurodegenerative disorders.

scholarly journals A20 prevents inflammasome-dependent arthritis by inhibiting macrophage necroptosis through its ZnF7 ubiquitin-binding domain

2019 ◽  
Vol 21 (6) ◽  
pp. 731-742 ◽  
Author(s):  
Apostolos Polykratis ◽  
Arne Martens ◽  
Remzi Onur Eren ◽  
Yoshitaka Shirasaki ◽  
Mai Yamagishi ◽  
...  
Keyword(s):  
Binding Domain ◽  
Ubiquitin Binding ◽  
Ubiquitin Binding Domain

scholarly journals CoCUN, a Novel Ubiquitin Binding Domain Identified in N4BP1

Biomolecules ◽  
2019 ◽  
Vol 9 (7) ◽  
pp. 284 ◽  
Author(s):  
Ridvan Nepravishta ◽  
Federica Ferrentino ◽  
Walter Mandaliti ◽  
Anna Mattioni ◽  
Janine Weber ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Structural Model ◽  
Functional Characterization ◽  
Binding Domain ◽  
15N Nmr ◽  
Protein Sequence Analysis ◽  
Hydrophobic Patch ◽  
Binding Domains ◽  
Ubiquitin Binding ◽  
Ubiquitin Binding Domain

Ubiquitin binding domains (UBDs) are modular elements that bind non-covalently to ubiquitin and act as downstream effectors and amplifiers of the ubiquitination signal. With few exceptions, UBDs recognize the hydrophobic path centered on Ile44, including residues Leu8, Ile44, His68, and Val70. A variety of different orientations, which can be attributed to specific contacts between each UBD and surface residues surrounding the hydrophobic patch, specify how each class of UBD specifically contacts ubiquitin. Here, we describe the structural model of a novel ubiquitin-binding domain that we identified in NEDD4 binding protein 1 (N4BP1). By performing protein sequence analysis, mutagenesis, and nuclear magnetic resonance (NMR) spectroscopy of the 15N isotopically labeled protein, we demonstrate that a Phe-Pro motif in N4BP1 recognizes the canonical hydrophobic patch of ubiquitin. This recognition mode resembles the molecular mechanism evolved in the coupling of ubiquitin conjugation to endoplasmic-reticulum (ER) degradation (CUE) domain family, where an invariant proline, usually following a phenylalanine, is required for ubiquitin binding. Interestingly, this novel UBD, which is not evolutionary related to CUE domains, shares a 40% identity and 47% similarity with cullin binding domain associating with NEDD8 (CUBAN), a protein module that also recognizes the ubiquitin-like NEDD8. Based on these features, we dubbed the region spanning the C-terminal 50 residues of N4BP1 the CoCUN domain, for Cousin of CUBAN. By performing circular dichroism and 15N NMR chemical shift perturbation of N4BP1 in complex with ubiquitin, we demonstrate that the CoCUN domain lacks the NEDD8 binding properties observed in CUBAN. We also show that, in addition to mediating the interaction with ubiquitin and ubiquitinated substrates, both CUBAN and CoCUN are poly-ubiquitinated in cells. The structural and the functional characterization of this novel UBD can contribute to a deeper understanding of the molecular mechanisms governing N4BP1 function, providing at the same time a valuable tool for clarifying how the discrimination between ubiquitin and the highly related NEDD8 is achieved.

Gfi1 ubiquitination and proteasomal degradation is inhibited by the ubiquitin ligase Triad1

Blood ◽  
2007 ◽  
Vol 110 (9) ◽  
pp. 3128-3135 ◽  
Author(s):  
Jurgen A. F. Marteijn ◽  
Laurens T. van der Meer ◽  
Liesbeth van Emst ◽  
Simon van Reijmersdal ◽  
Willemijn Wissink ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Ubiquitin Ligase ◽  
Ubiquitin Proteasome System ◽  
Proteasomal Degradation ◽  
Binding Domain ◽  
U937 Cells ◽  
Dna Binding Domain ◽  
Protein Levels ◽  
Ubiquitin Ligase Activity ◽  
Ubiquitin Proteasome

Abstract Growth factor independence 1 (Gfi1) is a transcriptional repressor essential for the function and development of many different hematopoietic lineages. The Gfi1 protein expression is regulated by the ubiquitin-proteasome system. In granulocytes, Gfi1 is rapidly degraded by the proteasome, while it is more stable in monocytes. How the ubiquitination and degradation of Gfi1 is regulated is unclear. Here, we show that the ubiquitin ligase Triad1 interacts with the DNA-binding domain of Gfi1. Unexpectedly, we found that Triad1 inhibited Gfi1 ubiquitination, resulting in a prolonged half-life. Down-regulation of endogenous Triad1 by siRNAs resulted in increased Gfi1 ubiquitination. In U937 cells, Triad1 caused an increase in endogenous Gfi1 protein levels and slowed cell proliferation in a similar manner when Gfi1 itself was expressed. A Triad1 mutant that lacks the Gfi1-binding domain did not affect Gfi1 levels and proliferation. Because neither proteasome-ubiquitin nor Triad1 ubiquitin ligase activity was required for the inhibition of Gfi1 ubiquitination, these data suggest that Triad1 competes for Gfi1 binding with as yet to be identified E3 ubiquitin ligases that do mark Gfi1 for proteasomal degradation. The finetuning of Gfi1 protein levels regulated by Triad1 defines an unexpected role for this protein in hematopoiesis.

scholarly journals Role of the ubiquitin-binding domain of Polη in Rad18-independent translesion DNA synthesis in human cell extracts

2010 ◽  
Vol 38 (19) ◽  
pp. 6456-6465 ◽  
Author(s):  
Valérie Schmutz ◽  
Régine Janel-Bintz ◽  
Jérôme Wagner ◽  
Denis Biard ◽  
Naoko Shiomi ◽  
...  
Keyword(s):  
Dna Synthesis ◽  
Human Cell ◽  
Binding Domain ◽  
Translesion Dna Synthesis ◽  
Cell Extracts ◽  
Ubiquitin Binding ◽  
Ubiquitin Binding Domain ◽  
Translesion Dna
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