The Roles of Ubiquitin-Binding Protein Shuttles in the Degradative Fate of Ubiquitinated Proteins in the Ubiquitin-Proteasome System and Autophagy

The ubiquitin-proteasome system (UPS) and autophagy are the two major intracellular protein quality control (PQC) pathways that are responsible for cellular proteostasis (homeostasis of the proteome) by ensuring the timely degradation of misfolded, damaged, and unwanted proteins. Ubiquitination serves as the degradation signal in both these systems, but substrates are precisely targeted to one or the other pathway. Determining how and when cells target specific proteins to these two alternative PQC pathways and control the crosstalk between them are topics of considerable interest. The ubiquitin (Ub) recognition code based on the type of Ub-linked chains on substrate proteins was believed to play a pivotal role in this process, but an increasing body of evidence indicates that the PQC pathway choice is also made based on other criteria. These include the oligomeric state of the Ub-binding protein shuttles, their conformation, protein modifications, and the presence of motifs that interact with ATG8/LC3/GABARAP (autophagy-related protein 8/microtubule-associated protein 1A/1B-light chain 3/GABA type A receptor-associated protein) protein family members. In this review, we summarize the current knowledge regarding the Ub recognition code that is bound by Ub-binding proteasomal and autophagic receptors. We also discuss how cells can modify substrate fate by modulating the structure, conformation, and physical properties of these receptors to affect their shuttling between both degradation pathways.

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Co-Chaperones in Targeting and Delivery of Misfolded Proteins to the 26S Proteasome

Biomolecules ◽

10.3390/biom10081141 ◽

2020 ◽

Vol 10 (8) ◽

pp. 1141 ◽

Cited By ~ 1

Author(s):

Amanda B. Abildgaard ◽

Sarah K. Gersing ◽

Sven Larsen-Ledet ◽

Sofie V. Nielsen ◽

Amelie Stein ◽

...

Keyword(s):

Protein Quality ◽

Current Knowledge ◽

Ubiquitin Proteasome System ◽

26S Proteasome ◽

Misfolded Proteins ◽

Nucleotide Exchange ◽

Nucleotide Exchange Factors ◽

Ubiquitin Proteasome ◽

Underlying Mechanisms ◽

The Individual

Protein homeostasis (proteostasis) is essential for the cell and is maintained by a highly conserved protein quality control (PQC) system, which triages newly synthesized, mislocalized and misfolded proteins. The ubiquitin-proteasome system (UPS), molecular chaperones, and co-chaperones are vital PQC elements that work together to facilitate degradation of misfolded and toxic protein species through the 26S proteasome. However, the underlying mechanisms are complex and remain partly unclear. Here, we provide an overview of the current knowledge on the co-chaperones that directly take part in targeting and delivery of PQC substrates for degradation. While J-domain proteins (JDPs) target substrates for the heat shock protein 70 (HSP70) chaperones, nucleotide-exchange factors (NEFs) deliver HSP70-bound substrates to the proteasome. So far, three NEFs have been established in proteasomal delivery: HSP110 and the ubiquitin-like (UBL) domain proteins BAG-1 and BAG-6, the latter acting as a chaperone itself and carrying its substrates directly to the proteasome. A better understanding of the individual delivery pathways will improve our ability to regulate the triage, and thus regulate the fate of aberrant proteins involved in cell stress and disease, examples of which are given throughout the review.

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Breakdown of Filamentous Myofibrils by the UPS–Step by Step

Biomolecules ◽

10.3390/biom11010110 ◽

2021 ◽

Vol 11 (1) ◽

pp. 110

Author(s):

Dina Aweida ◽

Shenhav Cohen

Keyword(s):

Protein Quality ◽

Protein Structures ◽

Ubiquitin Proteasome System ◽

Surface Proteins ◽

Catalytic Core ◽

Complex Protein ◽

Ubiquitin Proteasome ◽

Aaa Atpases

Protein degradation maintains cellular integrity by regulating virtually all biological processes, whereas impaired proteolysis perturbs protein quality control, and often leads to human disease. Two major proteolytic systems are responsible for protein breakdown in all cells: autophagy, which facilitates the loss of organelles, protein aggregates, and cell surface proteins; and the ubiquitin-proteasome system (UPS), which promotes degradation of mainly soluble proteins. Recent findings indicate that more complex protein structures, such as filamentous assemblies, which are not accessible to the catalytic core of the proteasome in vitro, can be efficiently degraded by this proteolytic machinery in systemic catabolic states in vivo. Mechanisms that loosen the filamentous structure seem to be activated first, hence increasing the accessibility of protein constituents to the UPS. In this review, we will discuss the mechanisms underlying the disassembly and loss of the intricate insoluble filamentous myofibrils, which are responsible for muscle contraction, and whose degradation by the UPS causes weakness and disability in aging and disease. Several lines of evidence indicate that myofibril breakdown occurs in a strictly ordered and controlled manner, and the function of AAA-ATPases is crucial for their disassembly and loss.

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

Cellular and Molecular Neurobiology ◽

10.1007/s10571-021-01060-z ◽

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.

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

Cells ◽

10.3390/cells10020283 ◽

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.

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

Molecular Biology of the Cell ◽

10.1091/mbc.e15-10-0697 ◽

2016 ◽

Vol 27 (8) ◽

pp. 1210-1219 ◽

Cited By ~ 18

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.

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The Ubiquitin Proteasome System in Ischemic and Dilated Cardiomyopathy

International Journal of Molecular Sciences ◽

10.3390/ijms20246354 ◽

2019 ◽

Vol 20 (24) ◽

pp. 6354 ◽

Cited By ~ 4

Author(s):

Sabine Spänig ◽

Kristina Kellermann ◽

Maja-Theresa Dieterlen ◽

Thilo Noack ◽

Sven Lehmann ◽

...

Keyword(s):

Protein Expression ◽

Ubiquitin Proteasome System ◽

Translation Initiation Factor ◽

Myocardial Tissue ◽

Activation Markers ◽

E3 Ligases ◽

Proteasomal Activity ◽

Ubiquitin Proteasome ◽

Statistical Trends ◽

And Control

Dilated (DCM) and ischemic cardiomyopathies (ICM) are associated with cardiac remodeling, where the ubiquitin–proteasome system (UPS) holds a central role. Little is known about the UPS and its alterations in patients suffering from DCM or ICM. The aim of this study is to characterize the UPS activity in human heart tissue from cardiomyopathy patients. Myocardial tissue from ICM (n = 23), DCM (n = 28), and control (n = 14) patients were used to quantify ubiquitinylated proteins, E3-ubiquitin-ligases muscle-atrophy-F-box (MAFbx)/atrogin-1, muscle-RING-finger-1 (MuRF1), and eukaryotic-translation-initiation-factor-4E (eIF4E), by Western blot. Furthermore, the proteasomal chymotrypsin-like and trypsin-like peptidase activities were determined fluorometrically. Enzyme activity of NAD(P)H oxidase was assessed as an index of reactive oxygen species production. The chymotrypsin- (p = 0.71) and caspase-like proteasomal activity (p = 0.93) was similar between the groups. Trypsin-like proteasomal activity was lower in ICM (0.78 ± 0.11 µU/mg) compared to DCM (1.06 ± 0.08 µU/mg) and control (1.00 ± 0.06 µU/mg; p = 0.06) samples. Decreased ubiquitin expression in both cardiomyopathy groups (ICM vs. control: p < 0.001; DCM vs. control: p < 0.001), as well as less ubiquitin-positive deposits in ICM-damaged tissue (ICM: 4.19% ± 0.60%, control: 6.28% ± 0.40%, p = 0.022), were detected. E3-ligase MuRF1 protein expression (p = 0.62), NADPH-oxidase activity (p = 0.63), and AIF-positive cells (p = 0.50). Statistical trends were detected for reduced MAFbx protein expression in the DCM-group (p = 0.07). Different levels of UPS components, E3 ligases, and UPS activation markers were observed in myocardial tissue from patients affected by DCM and ICM, suggesting differential involvement of the UPS in the underlying pathologies.

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Protein Quality Control in Neurodegeneration and Neuroprotection

Quality Control of Cellular Protein in Neurodegenerative Disorders - Advances in Medical Diagnosis, Treatment, and Care ◽

10.4018/978-1-7998-1317-0.ch001 ◽

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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Protein Quality Control Degradation in the Nucleus

Annual Review of Biochemistry ◽

10.1146/annurev-biochem-062917-012730 ◽

2018 ◽

Vol 87 (1) ◽

pp. 725-749 ◽

Cited By ~ 20

Author(s):

Charisma Enam ◽

Yifat Geffen ◽

Tommer Ravid ◽

Richard G. Gardner

Keyword(s):

Quality Control ◽

Protein Misfolding ◽

Protein Quality ◽

Current Knowledge ◽

Protein Quality Control ◽

Ubiquitin Proteasome System ◽

Misfolded Proteins ◽

Cellular Processes ◽

Human Disorders ◽

Protein Misfolding And Aggregation

Nuclear proteins participate in diverse cellular processes, many of which are essential for cell survival and viability. To maintain optimal nuclear physiology, the cell employs the ubiquitin-proteasome system to eliminate damaged and misfolded proteins in the nucleus that could otherwise harm the cell. In this review, we highlight the current knowledge about the major ubiquitin-protein ligases involved in protein quality control degradation (PQCD) in the nucleus and how they orchestrate their functions to eliminate misfolded proteins in different nuclear subcompartments. Many human disorders are causally linked to protein misfolding in the nucleus, hence we discuss major concepts that still need to be clarified to better understand the basis of the nuclear misfolded proteins’ toxic effects. Additionally, we touch upon potential strategies for manipulating nuclear PQCD pathways to ameliorate diseases associated with protein misfolding and aggregation in the nucleus.

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Aggregation and Prion-Inducing Properties of the G-Protein Gamma Subunit Ste18 are Regulated by Membrane Association

International Journal of Molecular Sciences ◽

10.3390/ijms21145038 ◽

2020 ◽

Vol 21 (14) ◽

pp. 5038

Author(s):

Tatiana A. Chernova ◽

Zhen Yang ◽

Tatiana S. Karpova ◽

John R. Shanks ◽

Natalia Shcherbik ◽

...

Keyword(s):

G Protein ◽

De Novo ◽

Ubiquitin Proteasome System ◽

Membrane Association ◽

Protein Assemblies ◽

Gamma Subunit ◽

Yeast Prions ◽

Extracellular Stimuli ◽

Ubiquitin Proteasome ◽

And Control

Yeast prions and mnemons are respectively transmissible and non-transmissible self-perpetuating protein assemblies, frequently based on cross-β ordered detergent-resistant aggregates (amyloids). Prions cause devastating diseases in mammals and control heritable traits in yeast. It was shown that the de novo formation of the prion form [PSI+] of yeast release factor Sup35 is facilitated by aggregates of other proteins. Here we explore the mechanism of the promotion of [PSI+] formation by Ste18, an evolutionarily conserved gamma subunit of a G-protein coupled receptor, a key player in responses to extracellular stimuli. Ste18 forms detergent-resistant aggregates, some of which are colocalized with de novo generated Sup35 aggregates. Membrane association of Ste18 is required for both Ste18 aggregation and [PSI+] induction, while functional interactions involved in signal transduction are not essential for these processes. This emphasizes the significance of a specific location for the nucleation of protein aggregation. In contrast to typical prions, Ste18 aggregates do not show a pattern of heritability. Our finding that Ste18 levels are regulated by the ubiquitin-proteasome system, in conjunction with the previously reported increase in Ste18 levels upon the exposure to mating pheromone, suggests that the concentration-dependent Ste18 aggregation may mediate a mnemon-like response to physiological stimuli.

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