scholarly journals Proteasome-associated ubiquitin ligase relays target plant hormone-specific transcriptional activators

2021 ◽  
Author(s):  
Zhishuo Wang ◽  
Beatriz Orosa-Puente ◽  
Mika Nomoto ◽  
Heather Grey ◽  
Thomas Potuschak ◽  
...  
Keyword(s):  
Ubiquitin Ligase ◽  
Stress Responses ◽  
Plant Hormone ◽  
Ubiquitin Ligases ◽  
Ubiquitin Proteasome System ◽  
Transcriptional Activators ◽  
Sequential Action ◽  
Ubiquitin Proteasome ◽  
Universal Mechanism ◽  
Target Plant

The ubiquitin-proteasome system is vital to hormone-mediated developmental and stress responses in plants. Ubiquitin ligases target hormone-specific transcriptional activators (TAs) for degradation, but how TAs are processed by proteasomes remains unknown. We report that in Arabidopsis the salicylic acid- and ethylene-responsive TAs, NPR1 and EIN3, are relayed from pathway-specific ubiquitin ligases to proteasome-associated HECT-type UPL3/4 ligases. Activity and stability of NPR1 was regulated by sequential action of three ubiquitin ligases, including UPL3/4, while proteasome processing of EIN3 required physical handover between ethylene-responsive SCFEBF2 and UPL3/4 ligases. Consequently, UPL3/4 controlled extensive hormone-induced developmental and stress-responsive transcriptional programmes. Thus, our findings identify unknown ubiquitin ligase relays that terminate with proteasome-associated HECT-type ligases, which may be a universal mechanism for processive degradation of proteasome-targeted TAs and other substrates.

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 Interaction between Parkin and α-Synuclein in PARK2-Mediated Parkinson’s Disease

Cells ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 283
Author(s):  
Daniel Aghaie Madsen ◽  
Sissel Ida Schmidt ◽  
Morten Blaabjerg ◽  
Morten Meyer
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Ubiquitin Ligase ◽  
Current Knowledge ◽  
Lewy Bodies ◽  
Ubiquitin Proteasome System ◽  
Loss Of Function ◽  
Functional Interaction ◽  
Future Studies ◽  
Ubiquitin Proteasome

Parkin and α-synuclein are two key proteins involved in the pathophysiology of Parkinson’s disease (PD). Neurotoxic alterations of α-synuclein that lead to the formation of toxic oligomers and fibrils contribute to PD through synaptic dysfunction, mitochondrial impairment, defective endoplasmic reticulum and Golgi function, and nuclear dysfunction. In half of the cases, the recessively inherited early-onset PD is caused by loss of function mutations in the PARK2 gene that encodes the E3-ubiquitin ligase, parkin. Parkin is involved in the clearance of misfolded and aggregated proteins by the ubiquitin-proteasome system and regulates mitophagy and mitochondrial biogenesis. PARK2-related PD is generally thought not to be associated with Lewy body formation although it is a neuropathological hallmark of PD. In this review article, we provide an overview of post-mortem neuropathological examinations of PARK2 patients and present the current knowledge of a functional interaction between parkin and α-synuclein in the regulation of protein aggregates including Lewy bodies. Furthermore, we describe prevailing hypotheses about the formation of intracellular micro-aggregates (synuclein inclusions) that might be more likely than Lewy bodies to occur in PARK2-related PD. This information may inform future studies aiming to unveil primary signaling processes involved in PD and related neurodegenerative disorders.

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 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.

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 Rotavirus NSP1 Associates with Components of the Cullin RING Ligase Family of E3 Ubiquitin Ligases

2016 ◽  
Vol 90 (13) ◽  
pp. 6036-6048 ◽  
Author(s):  
Lindy M. Lutz ◽  
Chandler R. Pace ◽  
Michelle M. Arnold
Keyword(s):  
Mass Spectrometry ◽  
Ubiquitin Ligase ◽  
Nonstructural Protein ◽  
Ubiquitin Proteasome System ◽  
Scaffolding Proteins ◽  
Target Proteins ◽  
Rotavirus A ◽  
Ubiquitin Proteasome ◽  
Infected Cells

ABSTRACTThe rotavirus nonstructural protein NSP1 acts as an antagonist of the host antiviral response by inducing degradation of key proteins required to activate interferon (IFN) production. Protein degradation induced by NSP1 is dependent on the proteasome, and the presence of a RING domain near the N terminus has led to the hypothesis that NSP1 is an E3 ubiquitin ligase. To examine this hypothesis, pulldown assays were performed, followed by mass spectrometry to identify components of the host ubiquitination machinery that associate with NSP1. Multiple components of cullin RING ligases (CRLs), which are essential multisubunit ubiquitination complexes, were identified in association with NSP1. The mass spectrometry was validated in both transfected and infected cells to show that the NSP1 proteins from different strains of rotavirus associated with key components of CRL complexes, most notably the cullin scaffolding proteins Cul3 and Cul1.In vitrobinding assays using purified proteins confirmed that NSP1 specifically interacted with Cul3 and that the N-terminal region of Cul3 was responsible for binding to NSP1. To test if NSP1 used CRL3 to induce degradation of the target protein IRF3 or β-TrCP, Cul3 levels were knocked down using a small interfering RNA (siRNA) approach. Unexpectedly, loss of Cul3 did not rescue IRF3 or β-TrCP from degradation in infected cells. The results indicate that, rather than actively using CRL complexes to induce degradation of target proteins required for IFN production, NSP1 may use cullin-containing complexes to prevent another cellular activity.IMPORTANCEThe ubiquitin-proteasome pathway plays an important regulatory role in numerous cellular functions, and many viruses have evolved mechanisms to exploit or manipulate this pathway to enhance replication and spread. Rotavirus, a major cause of severe gastroenteritis in young children that causes approximately 420,000 deaths worldwide each year, utilizes the ubiquitin-proteasome system to subvert the host innate immune response by inducing the degradation of key components required for the production of interferon (IFN). Here, we show that NSP1 proteins from different rotavirus strains associate with the scaffolding proteins Cul1 and Cul3 of CRL ubiquitin ligase complexes. Nonetheless, knockdown of Cul1 and Cul3 suggests that NSP1 induces the degradation of some target proteins independently of its association with CRL complexes, stressing a need to further investigate the mechanistic details of how NSP1 subverts the host IFN response.

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 Strategies for the identification of ubiquitin ligase inhibitors

2010 ◽  
Vol 38 (1) ◽  
pp. 132-136 ◽  
Author(s):  
Seth J. Goldenberg ◽  
Jeffrey G. Marblestone ◽  
Michael R. Mattern ◽  
Benjamin Nicholson
Keyword(s):  
Ubiquitin Ligase ◽  
Therapeutic Target ◽  
Therapeutic Strategy ◽  
Ubiquitin Proteasome System ◽  
Advantages And Disadvantages ◽  
Wide Range ◽  
Attractive Therapeutic Target ◽  
Ubiquitin Proteasome ◽  
Effective Therapeutic Strategy ◽  
Protein Ligases

Dysregulation of the UPS (ubiquitin–proteasome system) has been implicated in a wide range of pathologies including cancer, neurodegeneration and viral infection. Inhibiting the proteasome has been shown to be an effective therapeutic strategy in humans; however, toxicity with this target remains high. E3s (Ub–protein ligases) represent an alternative attractive therapeutic target in the UPS. In this paper, we will discuss current platforms that report on E3 ligase activity and can detect E3 inhibitors, and underline the advantages and disadvantages of each approach.

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