scholarly journals The Deubiquitylating Enzyme Ubp12 Regulates Rad23-Dependent Substrate Delivery at the Proteasome

2017 ◽  
Author(s):  
Daniela Gödderz ◽  
Nico P. Dantuma
Keyword(s):  
Dna Repair ◽  
Ubiquitin Proteasome System ◽  
Proteasomal Degradation ◽  
Misfolded Proteins ◽  
Proteotoxic Stress ◽  
Lysine Residues ◽  
Regulatory Link ◽  
Ubiquitin Proteasome ◽  
Summary Statement

AbstractThe consecutive actions of the ubiquitin-selective segregase Cdc48 and the ubiquitin shuttle factor Rad23 result in the delivery of ubiquitylated proteins at the proteasome. Here, we show that the deubiquitylating enzyme Ubp12 interacts with Cdc48 and regulates proteasomal degradation of Rad23-dependent substrates. Overexpression of Ubp12 results in stabilization of Rad23-dependent substrates. We show that Ubp12 removes short ubiquitin chains from the N-terminal ubiquitin-like domain (UbL) of Rad23. Preventing ubiquitylation of Rad23 by substitution of lysine residues within the UbL domain, Rad23UbLK0, does not affect the non-proteolytic role of Rad23 in DNA repair but causes an increase in ubiquitylated cargo bound to the UBA2 domains of Rad23 and recapitulates the stabilization of Rad23-dependent substrates observed upon overexpression of Ubp12. Expression of Rad23UbLK0or overexpression of Ubp12 impairs the ability of yeast to cope with proteotoxic stress consistent with inefficient clearance of misfolded proteins by the ubiquitin/proteasome system. Our data suggest that ubiquitylation of Rad23 plays a stimulatory role in facilitating the transfer of ubiquitylated substrates to the proteasome.Summary statementUbiquitylation of a ubiquitin shuttle factor regulates the delivery of substrates at the proteasome, uncovering a novel regulatory link between ubiquitin and proteasomal degradation.

scholarly journals PDE1 inhibition facilitates proteasomal degradation of misfolded proteins and protects against cardiac proteinopathy

2019 ◽  
Vol 5 (5) ◽  
pp. eaaw5870 ◽  
Author(s):  
Hanming Zhang ◽  
Bo Pan ◽  
Penglong Wu ◽  
Nirmal Parajuli ◽  
Mark D. Rekhter ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Ubiquitin Proteasome System ◽  
Proteasomal Degradation ◽  
Current Treatment ◽  
Misfolded Proteins ◽  
Dependent Protein Kinase ◽  
Selective Degradation ◽  
Proteotoxic Stress ◽  
Ubiquitin Proteasome ◽  
Dependent Protein

No current treatment targets cardiac proteotoxicity or can reduce mortality of heart failure (HF) with preserved ejection fraction (HFpEF). Selective degradation of misfolded proteins by the ubiquitin-proteasome system (UPS) is vital to the cell. Proteasome impairment contributes to HF. Activation of cAMP-dependent protein kinase (PKA) or cGMP-dependent protein kinase (PKG) facilitates proteasome functioning. Phosphodiesterase 1 (PDE1) hydrolyzes both cyclic nucleotides and accounts for most PDE activities in human myocardium. We report that PDE1 inhibition (IC86430) increases myocardial 26S proteasome activities and UPS proteolytic function in mice. Mice with CryABR120G-based proteinopathy develop HFpEF and show increased myocardial PDE1A expression. PDE1 inhibition markedly attenuates HFpEF, improves mouse survival, increases PKA-mediated proteasome phosphorylation, and reduces myocardial misfolded CryAB. Therefore, PDE1 inhibition induces PKA- and PKG-mediated promotion of proteasomal degradation of misfolded proteins and treats HFpEF caused by CryABR120G, representing a potentially new therapeutic strategy for HFpEF and heart disease with increased proteotoxic stress.

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 Parkin-mediated ubiquitin signalling in aggresome formation and autophagy

2010 ◽  
Vol 38 (1) ◽  
pp. 144-149 ◽  
Author(s):  
Lih-Shen Chin ◽  
James A. Olzmann ◽  
Lian Li
Keyword(s):  
Protein Misfolding ◽  
Current Knowledge ◽  
Ubiquitin Proteasome System ◽  
Misfolded Proteins ◽  
Proteotoxic Stress ◽  
Ubiquitin Proteasome ◽  
Autophagy Pathway ◽  
Aggresome Formation ◽  
Protein Misfolding And Aggregation ◽  
Cellular Defence

Understanding how cells handle and dispose of misfolded proteins is of paramount importance because protein misfolding and aggregation underlie the pathogenesis of many neurodegenerative disorders, including PD (Parkinson's disease) and Alzheimer's disease. In addition to the ubiquitin–proteasome system, the aggresome–autophagy pathway has emerged as another crucial cellular defence system against toxic build-up of misfolded proteins. In contrast with basal autophagy that mediates non-selective, bulk clearance of misfolded proteins along with normal cellular proteins and organelles, the aggresome–autophagy pathway is increasingly recognized as a specialized type of induced autophagy that mediates selective clearance of misfolded and aggregated proteins under the conditions of proteotoxic stress. Recent evidence implicates PD-linked E3 ligase parkin as a key regulator of the aggresome–autophagy pathway and indicates a signalling role for Lys63-linked polyubiquitination in the regulation of aggresome formation and autophagy. The present review summarizes the current knowledge of the aggresome–autophagy pathway, its regulation by parkin-mediated Lys63-linked polyubiquitination, and its dysfunction in neurodegenerative diseases.

scholarly journals TTC3-Mediated Protein Quality Control, A Potential Mechanism for Cognitive Impairment

2021 ◽  
Author(s):  
Xu Zhou ◽  
Xiongjin Chen ◽  
Tingting Hong ◽  
Miaoping Zhang ◽  
Yujie Cai ◽  
...  
Keyword(s):  
Quality Control ◽  
Cognitive Impairment ◽  
Protein Quality ◽  
Protein Quality Control ◽  
Ubiquitin Proteasome System ◽  
Research Progress ◽  
Repeat Domain ◽  
Ubiquitin Proteasome ◽  
Domain 3

AbstractThe tetrapeptide repeat domain 3 (TTC3) gene falls within Down's syndrome (DS) critical region. Cognitive impairment is a common phenotype of DS and Alzheimer’s disease (AD), and overexpression of TTC3 can accelerate cognitive decline, but the specific mechanism is unknown. The TTC3-mediated protein quality control (PQC) mechanism, similar to the PQC system, is divided into three parts: it acts as a cochaperone to assist proteins in folding correctly; it acts as an E3 ubiquitin ligase (E3s) involved in protein degradation processes through the ubiquitin–proteasome system (UPS); and it may also eventually cause autophagy by affecting mitochondrial function. Thus, this article reviews the research progress on the structure, function, and metabolism of TTC3, including the recent research progress on TTC3 in DS and AD; the role of TTC3 in cognitive impairment through PQC in combination with the abovementioned attributes of TTC3; and the potential targets of TTC3 in the treatment of such diseases.

scholarly journals Molecular switching from ubiquitin-proteasome to autophagy pathways in mice stroke model

2018 ◽  
Vol 40 (1) ◽  
pp. 214-224 ◽  
Author(s):  
Xia Liu ◽  
Toru Yamashita ◽  
Jingwei Shang ◽  
Xiaowen Shi ◽  
Ryuta Morihara ◽  
...  
Keyword(s):  
Cerebral Ischemia ◽  
Ubiquitin Proteasome System ◽  
Artery Occlusion ◽  
Misfolded Proteins ◽  
Molecular Switching ◽  
Pathological Conditions ◽  
Ubiquitin Proteasome ◽  
Ischemic Period ◽  
Mice Brain ◽  
Cerebral Artery Occlusion

The ubiquitin-proteasome system (UPS) and autophagy are two major pathways to degrade misfolded proteins that accumulate under pathological conditions. When UPS is overloaded, the degeneration pathway may switch to autophagy to remove excessive misfolded proteins. However, it is still unclear whether and how this switch occurs during cerebral ischemia. In the present study, transient middle cerebral artery occlusion (tMCAO) resulted in accelerated ubiquitin-positive protein aggregation from 0.5 h of reperfusion in mice brain after 10, 30 or 60 min of tMCAO. In contrast, significant reduction of p62 and induction of LC3-II were observed, peaking at 24 h of reperfusion after 30 and 60 min tMCAO. Western blot analyses showed an increase of BAG3 and HDAC6 at 1 or 24 h of reperfusion that was dependent on the ischemic period. In contract, BAG1 decreased at 24 h of reperfusion after 10, 30 or 60 min of tMCAO after double immunofluorescent colocalization of ubiquitin, HSP70, p62 and BAG3. These data suggest that a switch from UPS to autophagy occurred between 10 and 30 min of cerebral ischemia depending on the BAG1/BAG3 ratio and level of HDAC6.

scholarly journals Cytosolic splice isoform of Hsp70 nucleotide exchange factor Fes1 is required for the degradation of misfolded proteins in yeast

2016 ◽  
Vol 27 (8) ◽  
pp. 1210-1219 ◽  
Author(s):  
Naveen Kumar Chandappa Gowda ◽  
Jayasankar Mohanakrishnan Kaimal ◽  
Anna E. Masser ◽  
Wenjing Kang ◽  
Marc R. Friedländer ◽  
...  
Keyword(s):  
Elevated Temperatures ◽  
Protein Quality ◽  
Ectopic Expression ◽  
Ubiquitin Proteasome System ◽  
Misfolded Proteins ◽  
Control Mechanisms ◽  
Nucleotide Exchange ◽  
Exchange Factor ◽  
Nucleotide Exchange Factor ◽  
Ubiquitin Proteasome

Cells maintain proteostasis by selectively recognizing and targeting misfolded proteins for degradation. In Saccharomyces cerevisiae, the Hsp70 nucleotide exchange factor Fes1 is essential for the degradation of chaperone-associated misfolded proteins by the ubiquitin-proteasome system. Here we show that the FES1 transcript undergoes unique 3′ alternative splicing that results in two equally active isoforms with alternative C-termini, Fes1L and Fes1S. Fes1L is actively targeted to the nucleus and represents the first identified nuclear Hsp70 nucleotide exchange factor. In contrast, Fes1S localizes to the cytosol and is essential to maintain proteostasis. In the absence of Fes1S, the heat-shock response is constitutively induced at normally nonstressful conditions. Moreover, cells display severe growth defects when elevated temperatures, amino acid analogues, or the ectopic expression of misfolded proteins, induce protein misfolding. Importantly, misfolded proteins are not targeted for degradation by the ubiquitin-proteasome system. These observations support the notion that cytosolic Fes1S maintains proteostasis by supporting the removal of toxic misfolded proteins by proteasomal degradation. This study provides key findings for the understanding of the organization of protein quality control mechanisms in the cytosol and nucleus.

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.

Protein Quality Control in Neurodegeneration and Neuroprotection

2020 ◽  
pp. 1-24
Author(s):  
Yasmeena Akhter ◽  
Jahangir Nabi ◽  
Hinna Hamid ◽  
Nahida Tabassum ◽  
Faheem Hyder Pottoo ◽  
...  
Keyword(s):  
Quality Control ◽  
Neurodegenerative Disorders ◽  
Protein Quality ◽  
Protein Quality Control ◽  
Ubiquitin Proteasome System ◽  
Security System ◽  
Conformational Disorders ◽  
Ubiquitin Proteasome ◽  
Multi Level

Proteostasis is essential for regulating the integrity of the proteome. Disruption of proteostasis under some rigorous conditions leads to the aggregation and accumulation of misfolded toxic proteins, which plays a central role in the pathogenesis of protein conformational disorders. The protein quality control (PQC) system serves as a multi-level security system to shield cells from abnormal proteins. The intrinsic PQC systems maintaining proteostasis include the ubiquitin-proteasome system (UPS), chaperon-mediated autophagy (CMA), and autophagy-lysosome pathway (ALP) that serve to target misfolded proteins for unfolding, refolding, or degradation. Alterations of PQC systems in neurons have been implicated in the pathogenesis of various neurodegenerative disorders. This chapter provides an overview of PQC pathways to set a framework for discussion of the role of PQC in neurodegenerative disorders. Additionally, various pharmacological approaches targeting PQC are summarized.

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