scholarly journals Unstructured Biology of Proteins from Ubiquitin-Proteasome System: Roles in Cancer and Neurodegenerative Diseases

Biomolecules ◽  
2020 ◽  
Vol 10 (5) ◽  
pp. 796 ◽  
Author(s):  
Kundlik Gadhave ◽  
Prateek Kumar ◽  
Shivani Kapuganti ◽  
Vladimir Uversky ◽  
Rajanish Giri
Keyword(s):  
Intrinsically Disordered Protein ◽  
Intrinsic Disorder ◽  
Ubiquitin Proteasome System ◽  
Cellular Protein ◽  
26S Proteasome ◽  
Deubiquitinating Enzymes ◽  
Intrinsically Disordered ◽  
Anti Cancer ◽  
Ubiquitin Proteasome ◽  
Dependent Protein

The 26S proteasome is a large (~2.5 MDa) protein complex consisting of at least 33 different subunits and many other components, which form the ubiquitin proteasomal system (UPS), an ATP-dependent protein degradation system in the cell. UPS serves as an essential component of the cellular protein surveillance machinery, and its dysfunction leads to cancer, neurodegenerative and immunological disorders. Importantly, the functions and regulations of proteins are governed by the combination of ordered regions, intrinsically disordered protein regions (IDPRs) and molecular recognition features (MoRFs). The structure–function relationships of UPS components have not been identified completely; therefore, in this study, we have carried out the functional intrinsic disorder and MoRF analysis for potential neurodegenerative disease and anti-cancer targets of this pathway. Our report represents the presence of significant intrinsic disorder and disorder-based binding regions in several UPS proteins, such as extraproteasomal polyubiquitin receptors (UBQLN1 and UBQLN2), proteasome-associated polyubiquitin receptors (ADRM1 and PSMD4), deubiquitinating enzymes (DUBs) (ATXN3 and USP14), and ubiquitinating enzymes (E2 (UBE2R2) and E3 (STUB1) enzyme). We believe this study will have implications for the conformation-specific roles of different regions of these proteins. This will lead to a better understanding of the molecular basis of UPS-associated diseases.

scholarly journals p62-containing, proteolytically active nuclear condensates, increase the efficiency of the ubiquitin–proteasome system

2021 ◽  
Vol 118 (33) ◽  
pp. e2107321118
Author(s):  
Afu Fu ◽  
Victoria Cohen-Kaplan ◽  
Noa Avni ◽  
Ido Livneh ◽  
Aaron Ciechanover
Keyword(s):  
Ubiquitin Ligase ◽  
Protein Quality ◽  
Ubiquitin Proteasome System ◽  
Cellular Protein ◽  
26S Proteasome ◽  
Ubiquitin Chain ◽  
Recognition Element ◽  
Oxidative Stresses ◽  
Ubiquitin Ligase E3 ◽  
Ubiquitin Proteasome

Degradation of a protein by the ubiquitin–proteasome system (UPS) is a multistep process catalyzed by sequential reactions. Initially, ubiquitin is conjugated to the substrate in a process mediated by concerted activity of three enzymes; the last of them—a ubiquitin ligase (E3)—belongs to a family of several hundred members, each recognizing a few specific substrates. This is followed by repeated addition of ubiquitin moieties to the previously conjugated one to generate a ubiquitin chain that serves as a recognition element for the proteasome, which then degrades the substrate. Ubiquitin is recycled via the activity of deubiquitinating enzymes (DUBs). It stands to reason that efficiency of such a complex process would depend on colocalization of the different components in an assembly that allows the reactions to be carried out sequentially and processively. Here we describe nuclear condensates that are dynamic in their composition. They contain p62 as an essential component. These assemblies are generated by liquid–liquid phase separation (LLPS) and also contain ubiquitinated targets, 26S proteasome, the three conjugating enzymes, and DUBs. Under basal conditions, they serve as efficient centers for proteolysis of nuclear proteins (e.g., c-Myc) and unassembled subunits of the proteasome, suggesting they are involved in cellular protein quality control. Supporting this notion is the finding that such foci are also involved in degradation of misfolded proteins induced by heat and oxidative stresses, following recruitment of heat shock proteins and their associated ubiquitin ligase CHIP.

Targeting Protein Degradation in Cancer Treatment

2020 ◽  
Vol 14 ◽  
Author(s):  
Imane Bjij ◽  
Ismail Hdoufane ◽  
Mahmoud Soliman ◽  
Menče Najdoska-Bogdanov ◽  
Driss Cherqaoui
Keyword(s):  
Protein Degradation ◽  
Therapeutic Potential ◽  
Ubiquitin Proteasome System ◽  
Degradation Pathway ◽  
Cellular Protein ◽  
Cellular Level ◽  
Cancerous Cell ◽  
Promising Target ◽  
Anti Cancer ◽  
Ubiquitin Proteasome

: The ubiquitin proteasome system (UPS) is a crucial protein degradation pathway that involves several enzymes to maintain cellular protein homeostasis. This system has emerged as a major drug target against certain types of cancer as a disruption at the cellular level of UPS enzyme components forces the transformation of normal cell into cancerous cell. Although enormous advancements have been achieved in the understanding of tumorigenesis, efficient cancer therapy remains a goal towards alleviating this serious health issue. Since UPS has become a promising target for anticancer therapies, herein we provide comprehensive review of the ubiquitin proteasome system as a significant process for protein degradation. Herein, the anti-cancer therapeutic potential of this pathway is also discussed.

scholarly journals Proteasome inhibition in multiple myeloma: lessons for other cancers

2020 ◽  
Vol 318 (3) ◽  
pp. C451-C462 ◽  
Author(s):  
Paula Saavedra-García ◽  
Francesca Martini ◽  
Holger W. Auner
Keyword(s):  
Multiple Myeloma ◽  
Proteasome Inhibitors ◽  
Proteasome Inhibition ◽  
Ubiquitin Proteasome System ◽  
Cellular Protein ◽  
26S Proteasome ◽  
Cellular Functions ◽  
Glucose And Lipid Metabolism ◽  
Ubiquitin Proteasome ◽  
Cancer Multiple

Cellular protein homeostasis (proteostasis) depends on the controlled degradation of proteins that are damaged or no longer required by the ubiquitin-proteasome system (UPS). The 26S proteasome is the principal executer of substrate-specific proteolysis in eukaryotic cells and regulates a myriad of cellular functions. Proteasome inhibitors were initially developed as chemical tools to study proteasomal function but rapidly became widely used anticancer drugs that are now used at all stages of treatment for the bone marrow cancer multiple myeloma (MM). Here, we review the mechanisms of action of proteasome inhibitors that underlie their preferential toxicity to MM cells, focusing on endoplasmic reticulum stress, depletion of amino acids, and effects on glucose and lipid metabolism. We also discuss mechanisms of resistance to proteasome inhibition such as autophagy and metabolic rewiring and what lessons we may learn from the success and failure of proteasome inhibition in MM for treating other cancers with proteostasis-targeting drugs.

The therapeutic potential of deubiquitinating enzyme inhibitors

2010 ◽  
Vol 38 (1) ◽  
pp. 137-143 ◽  
Author(s):  
Frédéric Colland
Keyword(s):  
Anticancer Agents ◽  
Enzyme Inhibitors ◽  
Therapeutic Potential ◽  
Ubiquitin Proteasome System ◽  
Cellular Protein ◽  
Deubiquitinating Enzymes ◽  
Promising Alternative ◽  
Mantle Cell ◽  
Ubiquitin Proteasome ◽  
Ubiquitin Conjugation

Proteases play a key role in various pathological processes and several protease inhibitors are already available for treatment. DUBs (deubiquitinating enzymes) constitute one of the largest classes of human proteases and are key effectors of the ubiquitin–proteasome system. This pathway regulating cellular protein turnover has been implicated in the pathogenesis of many human diseases, including neurodegenerative disorders, viral diseases and cancer. The therapeutic efficacy of the proteasome inhibitor Velcade® (bortezomib) for treating multiple myeloma and mantle cell lymphoma establishes this system as a valid target for cancer treatment. A promising alternative to targeting the proteasome itself would be to target the upstream, ubiquitin conjugation/deconjugation system, to generate more specific, less toxic anticancer agents. Advances in small molecule-based inhibitors specifically targeting DUBs are presented in this review.

scholarly journals Accumulation of Mutant Huntingtin Fragments in Aggresome-like Inclusion Bodies as a Result of Insufficient Protein Degradation

2001 ◽  
Vol 12 (5) ◽  
pp. 1393-1407 ◽  
Author(s):  
Stephanie Waelter ◽  
Annett Boeddrich ◽  
Rudi Lurz ◽  
Eberhard Scherzinger ◽  
Gerhild Lueder ◽  
...  
Keyword(s):  
Inclusion Bodies ◽  
Rna Binding ◽  
Ubiquitin Proteasome System ◽  
26S Proteasome ◽  
Therapeutic Interventions ◽  
Ultrastructural Changes ◽  
Huntingtin Protein ◽  
Fibrillar Morphology ◽  
Exon 1 ◽  
Ubiquitin Proteasome

The huntingtin exon 1 proteins with a polyglutamine repeat in the pathological range (51 or 83 glutamines), but not with a polyglutamine tract in the normal range (20 glutamines), form aggresome-like perinuclear inclusions in human 293 Tet-Off cells. These structures contain aggregated, ubiquitinated huntingtin exon 1 protein with a characteristic fibrillar morphology. Inclusion bodies with truncated huntingtin protein are formed at centrosomes and are surrounded by vimentin filaments. Inhibition of proteasome activity resulted in a twofold increase in the amount of ubiquitinated, SDS-resistant aggregates, indicating that inclusion bodies accumulate when the capacity of the ubiquitin–proteasome system to degrade aggregation-prone huntingtin protein is exhausted. Immunofluorescence and electron microscopy with immunogold labeling revealed that the 20S, 19S, and 11S subunits of the 26S proteasome, the molecular chaperones BiP/GRP78, Hsp70, and Hsp40, as well as the RNA-binding protein TIA-1, the potential chaperone 14–3-3, and α-synuclein colocalize with the perinuclear inclusions. In 293 Tet-Off cells, inclusion body formation also resulted in cell toxicity and dramatic ultrastructural changes such as indentations and disruption of the nuclear envelope. Concentration of mitochondria around the inclusions and cytoplasmic vacuolation were also observed. Together these findings support the hypothesis that the ATP-dependent ubiquitin–proteasome system is a potential target for therapeutic interventions in glutamine repeat disorders.

scholarly journals Ccr4 is a novel shuttle factor required for ubiquitin-dependent proteolysis by the 26S proteasome

2020 ◽  
Author(s):  
Ganapathi Kandasamy ◽  
Ashis Kumar Pradhan ◽  
R Palanimurugan
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Protein Degradation ◽  
Ubiquitin Proteasome System ◽  
Proteasomal Degradation ◽  
Rna Degradation ◽  
26S Proteasome ◽  
Cellular Proteins ◽  
Cellular Homeostasis ◽  
Substrate Degradation ◽  
Ubiquitin Proteasome

AbstractDegradation of short-lived and abnormal proteins are essential for normal cellular homeostasis. In eukaryotes, such unstable cellular proteins are selectively degraded by the ubiquitin proteasome system (UPS). Furthermore, abnormalities in protein degradation by the UPS have been linked to several human diseases. Ccr4 protein is a known component of the Ccr4-Not complex, which has established roles in transcription, mRNA de-adenylation and RNA degradation etc. Excitingly in this study, we show that Ccr4 protein has a novel function as a shuttle factor that promotes ubiquitin-dependent degradation of short-lived proteins by the 26S proteasome. Using a substrate of the well-studied ubiquitin fusion degradation (UFD) pathway, we found that its UPS-mediated degradation was severely impaired upon deletion of CCR4 in Saccharomyces cerevisiae. Additionally, we show that Ccr4 binds to cellular ubiquitin conjugates and the proteasome. In contrast to Ccr4, most other subunits of the Ccr4-Not complex proteins are dispensable for UFD substrate degradation. From our findings we conclude that Ccr4 functions in the UPS as a shuttle factor targeting ubiquitylated substrates for proteasomal degradation.

scholarly journals Old players in new posts: the role of P53, ATM and DNAPK in DNA damage-related ubiquitylation-dependent removal of S2P RNAPII

2021 ◽  
Author(s):  
Barbara N Borsos ◽  
Vasiliki Pantazi ◽  
Zoltán G Páhi ◽  
Hajnalka Majoros ◽  
Zsuzsanna Ujfaludi ◽  
...  
Keyword(s):  
Dna Damage ◽  
Rna Polymerase Ii ◽  
E3 Ligase ◽  
Ubiquitin Proteasome System ◽  
Dna Double Strand Breaks ◽  
Damage Site ◽  
Strand Breaks ◽  
Cullin 3 ◽  
Ubiquitin Proteasome ◽  
Dependent Protein

AbstractDNA double-strand breaks are the most deleterious lesions for the cells, therefore understanding the macromolecular interactions in the DNA repair-related mechanisms is essential. DNA damage triggers transcription silencing at the damage site, leading to the removal of the elongating RNA polymerase II (S2P RNAPII) from this locus, which provides accessibility for the repair factors to the lesion. Ataxia-telangiectasia mutated (ATM) and DNA-dependent protein kinase (DNAPK) are the two main regulatory kinases of homologous recombination and non-homologous end joining, respectively. Although these kinases are involved in the activation of different repair pathways, they have common target proteins, such as P53. We previously demonstrated that following transcription block, P53 plays a pivotal role in transcription elongation process by interacting with S2P RNAPII. In the current study, we reveal that P53, ATM and DNAPK are involved in the fine-tune regulation of the ubiquitin-proteasome system-related degradation of S2P RNAPII. However, they act differently in this process: P53 delays the removal of S2P RNAPII, while ATM and DNAPK participate in the activation of members of E3 ligase complexes involved in the ubiquitylation of S2P RNAPII. We also demonstrate that WW domain-containing protein 2 (WWP2) and Cullin-3 (CUL3) are interaction partners of S2P RNAPII, thus forming a complex with the transcribing RNAPII complex.Simple SummaryTo ensure the proper repair following DNA double-strand breaks, the eviction of the arrested elongating RNA polymerase II (S2P RNAPII) is required. Here, we report an emerging role of P53, Ataxia-telangiectasia mutated (ATM) and DNA-dependent protein kinase (DNAPK) in the ubiquitin-proteasome system-dependent removal of S2P RNAPII. We also identified interactions between S2P RNAPII and WW domain-containing protein 2 (WWP2) or Cullin-3 (CUL3) (members of E3 ligase complexes), which are involved in the ubiquitylation of S2P RNAPII following DNA damage. Furthermore, the RNAPII-E3 ligase complex interactions are mediated by P53, ATM and DNAPK, which suggests potential participation of all three proteins in the effective resolution of transcription block at the damage site. Altogether, our results provide a better comprehension of the molecular background of transcription elongation block-related DNA repair processes and highlight an indispensable function of P53, ATM and DNAPK in these mechanisms.

scholarly journals Noncoding RNA MaIL1 is an integral component of the TLR4–TRIF pathway

2020 ◽  
Vol 117 (16) ◽  
pp. 9042-9053 ◽  
Author(s):  
Marina Aznaourova ◽  
Harshavardhan Janga ◽  
Stephanie Sefried ◽  
Andreas Kaufmann ◽  
Jens Dorna ◽  
...  
Keyword(s):  
Mammalian Cells ◽  
Noncoding Rna ◽  
Signal Transduction Pathway ◽  
Ubiquitin Proteasome System ◽  
Lavage Fluid ◽  
Cellular Protein ◽  
Type I ◽  
Toll Like Receptor 4 ◽  
Ubiquitin Proteasome ◽  
Highly Correlated

RNA has been proposed as an important scaffolding factor in the nucleus, aiding protein complex assembly in the dense intracellular milieu. Architectural contributions of RNA to cytosolic signaling pathways, however, remain largely unknown. Here, we devised a multidimensional gradient approach, which systematically locates RNA components within cellular protein networks. Among a subset of noncoding RNAs (ncRNAs) cosedimenting with the ubiquitin–proteasome system, our approach unveiled ncRNA MaIL1 as a critical structural component of the Toll-like receptor 4 (TLR4) immune signal transduction pathway. RNA affinity antisense purification–mass spectrometry (RAP-MS) revealed MaIL1 binding to optineurin (OPTN), a ubiquitin-adapter platforming TBK1 kinase. MaIL1 binding stabilized OPTN, and consequently, loss of MaIL1 blunted OPTN aggregation, TBK1-dependent IRF3 phosphorylation, and type I interferon (IFN) gene transcription downstream of TLR4. MaIL1 expression was elevated in patients with active pulmonary infection and was highly correlated with IFN levels in bronchoalveolar lavage fluid. Our study uncovers MaIL1 as an integral RNA component of the TLR4–TRIF pathway and predicts further RNAs to be required for assembly and progression of cytosolic signaling networks in mammalian cells.

scholarly journals Ubiquitin carboxyl-terminal hydrolases are required for period maintenance of the circadian clock at high temperature in Arabidopsis

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Ryosuke Hayama ◽  
Peizhen Yang ◽  
Federico Valverde ◽  
Tsuyoshi Mizoguchi ◽  
Ikuyo Furutani-Hayama ◽  
...  
Keyword(s):  
Circadian Clock ◽  
High Temperatures ◽  
Elevated Temperatures ◽  
Control Period ◽  
Ubiquitin Proteasome System ◽  
26S Proteasome ◽  
Cellular Processes ◽  
Control Functions ◽  
Ubiquitin Proteasome ◽  
Carboxyl Terminal

AbstractProtein ubiquitylation participates in a number of essential cellular processes including signal transduction and transcription, often by initiating the degradation of specific substrates through the 26S proteasome. Within the ubiquitin-proteasome system, deubiquitylating enzymes (DUBs) not only help generate and maintain the supply of free ubiquitin monomers, they also directly control functions and activities of specific target proteins by modulating the pool of ubiquitylated species. Ubiquitin carboxyl-terminal hydrolases (UCHs) belong to an enzymatic subclass of DUBs, and are represented by three members in Arabidopsis, UCH1, UCH2 and UCH3. UCH1 and UCH2 influence auxin-dependent developmental pathways in Arabidopsis through their deubiquitylation activities, whereas biological and enzymatic functions of UCH3 remain unclear. Here, we demonstrate that Arabidopsis UCH3 acts to maintain the period of the circadian clock at high temperatures redundantly with UCH1 and UCH2. Whereas single uch1, uch2 and uch3 mutants have weak circadian phenotypes, the triple uch mutant displays a drastic lengthening of period at high temperatures that is more extreme than the uch1 uch2 double mutant. UCH3 also possesses a broad deubiquitylation activity against a range of substrates that link ubiquitin via peptide and isopeptide linkages. While the protein target(s) of UCH1-3 are not yet known, we propose that these DUBs act on one or more factors that control period length of the circadian clock through removal of their bound ubiquitin moieties, thus ensuring that the clock oscillates with a proper period even at elevated temperatures.

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.

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