scholarly journals Huntingtin Ubiquitination Mechanisms and Novel Possible Therapies to Decrease the Toxic Effects of Mutated Huntingtin

2021 ◽  
Vol 11 (12) ◽  
pp. 1309
Author(s):  
Annarita Fiorillo ◽  
Veronica Morea ◽  
Gianni Colotti ◽  
Andrea Ilari
Keyword(s):  
Small Molecules ◽  
Ubiquitin Ligase ◽  
Neurodegenerative Disorder ◽  
E3 Ubiquitin Ligase ◽  
Ubiquitin Proteasome System ◽  
Aggregate Formation ◽  
Gene Encoding ◽  
Exon 1 ◽  
Ubiquitin Proteasome ◽  
Abnormal Expansion

Huntington Disease (HD) is a dominant, lethal neurodegenerative disorder caused by the abnormal expansion (>35 copies) of a CAG triplet located in exon 1 of the HTT gene encoding the huntingtin protein (Htt). Mutated Htt (mHtt) easily aggregates, thereby inducing ER stress that in turn leads to neuronal injury and apoptosis. Therefore, both the inhibition of mHtt aggregate formation and the acceleration of mHtt degradation represent attractive strategies to delay HD progression, and even for HD treatment. Here, we describe the mechanism underlying mHtt degradation by the ubiquitin–proteasome system (UPS), which has been shown to play a more important role than the autophagy–lysosomal pathway. In particular, we focus on E3 ligase proteins involved in the UPS and detail their structure–function relationships. In this framework, we discuss the possible exploitation of PROteolysis TArgeting Chimeras (PROTACs) for HD therapy. PROTACs are heterobifunctional small molecules that comprise two different ligands joined by an appropriate linker; one of the ligands is specific for a selected E3 ubiquitin ligase, the other ligand is able to recruit a target protein of interest, in this case mHtt. As a consequence of PROTAC binding, mHtt and the E3 ubiquitin ligase can be brought to a relative position that allows mHtt to be ubiquitinated and, ultimately, allows a reduction in the amount of mHtt in the cell.

scholarly journals Exploring the Ubiquitin-Proteasome System (UPS) through PROTAC Technology

2020 ◽  
Vol 74 (4) ◽  
pp. 274-277
Author(s):  
Carlotta Cecchini ◽  
Sébastien Tardy ◽  
Valentina Ceserani ◽  
Jean-Philippe Theurillat ◽  
Leonardo Scapozza
Keyword(s):  
Renal Cell Carcinoma ◽  
Small Molecules ◽  
Ubiquitin Ligase ◽  
Active Sites ◽  
E3 Ubiquitin Ligase ◽  
Ubiquitin Proteasome System ◽  
Classical Approach ◽  
Hypoxia Inducible Factors ◽  
Von Hippel Lindau ◽  
Ubiquitin Proteasome

In the context of dysregulated ubiquitylation, the accumulation of oncogenic substrates can lead to tumorigenesis. In particular, mutations in Von Hippel-Lindau (VHL) E3 ubiquitin ligase are related to overexpression of hypoxia-inducible factors (HIF-1α and HIF-2α) which is evolving into renal cell carcinoma (RCC). The classical approach of drug discovery focuses on the development of highly selective small molecules able to bind and to inhibit enzymatic active sites. This strategy faces limitations in the context of ' undruggable ' proteins, which are challenging to target. The discovery of Proteolysis Targeting Chimeras (PROTACs) as an alternative strategy to induce selective protein degradation is presented as a working hypothesis to understand further the UbiquitinProteasome System (UPS) and eventually counteract RCC cancer lacking VHL ubiquitin ligase.

scholarly journals p97 Negatively Regulates NRF2 by Extracting Ubiquitylated NRF2 from the KEAP1-CUL3 E3 Complex

2017 ◽  
Vol 37 (8) ◽  
Author(s):  
Shasha Tao ◽  
Pengfei Liu ◽  
Gang Luo ◽  
Montserrat Rojo de la Vega ◽  
Heping Chen ◽  
...  
Keyword(s):  
Ubiquitin Ligase ◽  
Protein Complexes ◽  
E3 Ubiquitin Ligase ◽  
Ubiquitin Proteasome System ◽  
Proteasomal Degradation ◽  
Ubiquitin Ligase Complex ◽  
Ubiquitin Proteasome ◽  
Client Proteins

ABSTRACT Activation of the stress-responsive transcription factor NRF2 is the major line of defense to combat oxidative or electrophilic insults. Under basal conditions, NRF2 is continuously ubiquitylated by the KEAP1-CUL3-RBX1 E3 ubiquitin ligase complex and is targeted to the proteasome for degradation (the canonical mechanism). However, the path from the CUL3 complex to ultimate proteasomal degradation was previously unknown. p97 is a ubiquitin-targeted ATP-dependent segregase that extracts ubiquitylated client proteins from membranes, protein complexes, or chromatin and has an essential role in autophagy and the ubiquitin proteasome system (UPS). In this study, we show that p97 negatively regulates NRF2 through the canonical pathway by extracting ubiquitylated NRF2 from the KEAP1-CUL3 E3 complex, with the aid of the heterodimeric cofactor UFD1/NPL4 and the UBA-UBX-containing protein UBXN7, for efficient proteasomal degradation. Given the role of NRF2 in chemoresistance and the surging interest in p97 inhibitors to treat cancers, our results indicate that dual p97/NRF2 inhibitors may offer a more potent and long-term avenue of p97-targeted treatment.

scholarly journals The E3 ubiquitin ligase UBR5 regulates centriolar satellite stability and primary cilia

2018 ◽  
Vol 29 (13) ◽  
pp. 1542-1554 ◽  
Author(s):  
Robert F. Shearer ◽  
Kari-Anne Myrum Frikstad ◽  
Jessie McKenna ◽  
Rachael A. McCloy ◽  
Niantao Deng ◽  
...  
Keyword(s):  
Ubiquitin Ligase ◽  
Developmental Disorders ◽  
Primary Cilia ◽  
E3 Ubiquitin Ligase ◽  
Ubiquitin Proteasome System ◽  
Interacting Protein ◽  
Robust Model ◽  
Cilia Formation ◽  
Cytoplasmic Organization ◽  
Ubiquitin Proteasome

Primary cilia are crucial for signal transduction in a variety of pathways, including hedgehog and Wnt. Disruption of primary cilia formation (ciliogenesis) is linked to numerous developmental disorders (known as ciliopathies) and diseases, including cancer. The ubiquitin–proteasome system (UPS) component UBR5 was previously identified as a putative positive regulator of ciliogenesis in a functional genomics screen. UBR5 is an E3 ubiquitin ligase that is frequently deregulated in tumors, but its biological role in cancer is largely uncharacterized, partly due to a lack of understanding of interacting proteins and pathways. We validated the effect of UBR5 depletion on primary cilia formation using a robust model of ciliogenesis, and identified CSPP1, a centrosomal and ciliary protein required for cilia formation, as a UBR5-interacting protein. We show that UBR5 ubiquitylates CSPP1, and that UBR5 is required for cytoplasmic organization of CSPP1-comprising centriolar satellites in centrosomal periphery, suggesting that UBR5-mediated ubiquitylation of CSPP1 or associated centriolar satellite constituents is one underlying requirement for cilia expression. Hence, we have established a key role for UBR5 in ciliogenesis that may have important implications in understanding cancer pathophysiology.

scholarly journals ZSCAN4 is negatively regulated by the ubiquitin-proteasome system and the E3 ubiquitin ligase RNF20

2018 ◽  
Vol 498 (1) ◽  
pp. 72-78 ◽  
Author(s):  
Benjamin A. Portney ◽  
Raju Khatri ◽  
W. Alex Meltzer ◽  
Jennifer M. Mariano ◽  
Michal Zalzman
Keyword(s):  
Ubiquitin Ligase ◽  
E3 Ubiquitin Ligase ◽  
Ubiquitin Proteasome System ◽  
Ubiquitin Proteasome

SCFβ-TRCP Mediates Ubiquitination and Degradation of the Erythropoietin Receptor and Controls Cell Proliferation.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 464-464
Author(s):  
Frederique Verdier ◽  
Laure Meyer ◽  
Benedicte Deau ◽  
Hana Forejtnikova ◽  
Dominique Dumenil ◽  
...  
Keyword(s):  
Binding Site ◽  
Ubiquitin Ligase ◽  
Blood Cells ◽  
E3 Ubiquitin Ligase ◽  
Ubiquitin Proteasome System ◽  
Erythropoietin Receptor ◽  
Erythroid Progenitors ◽  
Ubiquitin Proteasome ◽  
Binding Sequence ◽  
Stimulation Of

Abstract Control of intensity and duration of erythropoietin (Epo) signalling is necessary to tightly regulate red blood cells production. After Epo stimulation of erythroid cells, 2 types of signal are transduced via the Epo receptor (Epo-R): positive signals involved in survival and proliferation, and negative signals involved in signal arrest. We have recently shown that the ubiquitin/ proteasome system plays a major role in the control of Epo-R signalling duration and desensitisation processes. Indeed, after Epo stimulation the Epo-R is ubiquitinated and its intracellular part is degraded by the proteasome, preventing further signal transduction. The remaining part of the receptor, together with associated Epo is internalised and degraded by the lysosomes (Walrafen et al 2005 Blood, 105, 600-608). Our aim was to identify the E3 ubiquitin ligase involved in Epo-R ubiquitination. The Epo-R contains a putative β-Trcp binding site in its intracellular domain. Interestingly, this putative binding sequence is located in a region of the Epo-R that is deleted in erythroid progenitors from patients with familial polycythemia. We show that β-Trcp is responsible for Epo-R ubiquitination upon Epo stimulation. After Epo stimulation, β-Trcp binds to the Epo-R and this binding is dependent on Jak2 activation. Mutation of the Ser 462 residue of the Epo-R, located in the consensus β-Trcp binding site abolished β-Trcp binding, Epo-R ubiquitination and EpoR cleavage by the proteasome. Activation of the mutated Epo-R is prolonged in comparaison with Epo-R WT and BaF3 cells expressing this mutated receptor unable to bind β-Trcp are hypersensitive to Epo. Whether the removal of the β-Trcp binding site contributes to the hypersensitivity to Epo in familial polycythemia is currently under study.]

scholarly journals The Molecular and Pathophysiological Functions of Members of the LNX/PDZRN E3 Ubiquitin Ligase Family

Molecules ◽  
2020 ◽  
Vol 25 (24) ◽  
pp. 5938
Author(s):  
Jeongkwan Hong ◽  
Minho Won ◽  
Hyunju Ro
Keyword(s):  
Ubiquitin Ligase ◽  
E3 Ubiquitin Ligase ◽  
Ubiquitin Ligases ◽  
Ubiquitin Proteasome System ◽  
E3 Ubiquitin Ligases ◽  
Intercellular Signaling ◽  
Cellular Functions ◽  
Ring Type ◽  
Ubiquitin Ligase Activity ◽  
Ubiquitin Proteasome

The ligand of Numb protein-X (LNX) family, also known as the PDZRN family, is composed of four discrete RING-type E3 ubiquitin ligases (LNX1, LNX2, LNX3, and LNX4), and LNX5 which may not act as an E3 ubiquitin ligase owing to the lack of the RING domain. As the name implies, LNX1 and LNX2 were initially studied for exerting E3 ubiquitin ligase activity on their substrate Numb protein, whose stability was negatively regulated by LNX1 and LNX2 via the ubiquitin-proteasome pathway. LNX proteins may have versatile molecular, cellular, and developmental functions, considering the fact that besides these proteins, none of the E3 ubiquitin ligases have multiple PDZ (PSD95, DLGA, ZO-1) domains, which are regarded as important protein-interacting modules. Thus far, various proteins have been isolated as LNX-interacting proteins. Evidence from studies performed over the last two decades have suggested that members of the LNX family play various pathophysiological roles primarily by modulating the function of substrate proteins involved in several different intracellular or intercellular signaling cascades. As the binding partners of RING-type E3s, a large number of substrates of LNX proteins undergo degradation through ubiquitin-proteasome system (UPS) dependent or lysosomal pathways, potentially altering key signaling pathways. In this review, we highlight recent and relevant findings on the molecular and cellular functions of the members of the LNX family and discuss the role of the erroneous regulation of these proteins in disease progression.

scholarly journals TcpC inhibits toll-like receptor signaling pathway by serving as an E3 ubiquitin ligase that promotes degradation of myeloid differentiation factor 88

2021 ◽  
Vol 17 (3) ◽  
pp. e1009481
Author(s):  
Jia-qi Fang ◽  
Qian Ou ◽  
Jun Pan ◽  
Jie Fang ◽  
Da-yong Zhang ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Ubiquitin Ligase ◽  
Bacterial Pathogens ◽  
E3 Ubiquitin Ligase ◽  
Ubiquitin Proteasome System ◽  
Mrna Levels ◽  
Tlr Signaling ◽  
Protein Levels ◽  
Ubiquitin Proteasome ◽  
Myeloid Differentiation Factor

TcpC is a virulence factor of uropathogenic E. coli (UPEC). It was found that TIR domain of TcpC impedes TLR signaling by direct association with MyD88. It has been a long-standing question whether bacterial pathogens have evolved a mechanism to manipulate MyD88 degradation by ubiquitin-proteasome pathway. Here, we show that TcpC is a MyD88-targeted E3 ubiquitin ligase. Kidney macrophages from mice with pyelonephritis induced by TcpC-secreting UPEC showed significantly decreased MyD88 protein levels. Recombinant TcpC (rTcpC) dose-dependently inhibited protein but not mRNA levels of MyD88 in macrophages. Moreover, rTcpC significantly promoted MyD88 ubiquitination and accumulation in proteasomes in macrophages. Cys12 and Trp106 in TcpC are crucial amino acids in maintaining its E3 activity. Therefore, TcpC blocks TLR signaling pathway by degradation of MyD88 through ubiquitin-proteasome system. Our findings provide not only a novel biochemical mechanism underlying TcpC-medicated immune evasion, but also the first example that bacterial pathogens inhibit MyD88-mediated signaling pathway by virulence factors that function as E3 ubiquitin ligase.

scholarly journals The E3 ubiquitin ligase UBR5 regulates centriolar satellite stability and primary cilia formation via ubiquitylation of CSPP-L

2016 ◽  
Author(s):  
Robert F. Shearer ◽  
Kari-Anne Myrum Frikstad ◽  
Jessie McKenna ◽  
Rachael A. McCloy ◽  
Niantao Deng ◽  
...  
Keyword(s):  
Ubiquitin Ligase ◽  
Developmental Disorders ◽  
Primary Cilia ◽  
E3 Ubiquitin Ligase ◽  
Ubiquitin Proteasome System ◽  
Interacting Protein ◽  
Robust Model ◽  
Cilia Formation ◽  
Cytoplasmic Organization ◽  
Ubiquitin Proteasome

AbstractPrimary cilia are crucial for signal transduction in a variety of pathways, including Hedgehog and Wnt. Disruption of primary cilia formation (ciliogenesis) is linked to numerous developmental disorders (known as ciliopathies) and diseases, including cancer. The Ubiquitin-Proteasome System (UPS) component UBR5 was previously identified as a putative modulator of ciliogenesis in a functional genomics screen. UBR5 is an E3 Ubiquitin ligase that is frequently deregulated in tumours, but its biological role in cancer is largely uncharacterised, partly due to a lack of understanding of interacting proteins and pathways. We validated the effect of UBR5 depletion on primary cilia formation using a robust model of ciliogenesis, and identified CSPP1, a centrosomal and ciliary protein required for cilia formation, as a UBR5-interacting protein. We show that UBR5 ubiquitylates CSPP1, and that UBR5 is required for cytoplasmic organization of CSPP1-comprising centriolar satellites in centrosomal periphery. Hence, we have established a key role for UBR5 in ciliogenesis that may have important implications in understanding cancer pathophysiology.

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.

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