Proteostasis regulation by the ubiquitin system

2016 ◽  
Vol 60 (2) ◽  
pp. 143-151 ◽  
Author(s):  
John S. Bett
Keyword(s):  
Protein Misfolding ◽  
Amyotrophic Lateral Sclerosis Patient ◽  
Ubiquitin Proteasome System ◽  
Cellular Protein ◽  
Ubiquitin System ◽  
Ubiquitin Proteasome ◽  
Ad Alzheimer’S Disease ◽  
Cellular Phenotypes ◽  
Protein Misfolding And Aggregation ◽  
Lateral Sclerosis

Cells have developed an evolutionary obligation to survey and maintain proteome fidelity and avoid the possible toxic consequences of protein misfolding and aggregation. Disturbances to protein homoeostasis (proteostasis) can result in severe cellular phenotypes and are closely linked with the accumulation of microscopically visible deposits of aggregated proteins. These include inclusion bodies found in AD (Alzheimer's disease), HD (Huntington's disease) and ALS (amyotrophic lateral sclerosis) patient neurons. Protein aggregation is intimately linked with the ubiquitin and ubiquitin-like post-translational modifier system, which manages cellular protein folding stress and promotes the restoration of proteostasis. This is achieved in large part through the action of the UPS (ubiquitin–proteasome system), which is responsible for directing the proteasomal destruction of misfolded and damaged proteins tagged with ubiquitin chains. There are other less well understood ways in which ubiquitin family members can help to maintain proteostasis that complement, but are independent of, the UPS. This article discusses our current understanding of how the ubiquitin family regulates the protein misfolding pathways that threaten proteome fidelity, and how this is achieved by the key players in this process.

scholarly journals Dysregulation of the Autophagy-Endolysosomal System in Amyotrophic Lateral Sclerosis and Related Motor Neuron Diseases

2012 ◽  
Vol 2012 ◽  
pp. 1-12 ◽  
Author(s):  
Asako Otomo ◽  
Lei Pan ◽  
Shinji Hadano
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Motor Neuron ◽  
Motor Neurons ◽  
Protein Misfolding ◽  
Disease Onset ◽  
Ubiquitin Proteasome System ◽  
Protective Role ◽  
Motor Neuron Diseases ◽  
Ubiquitin Proteasome ◽  
Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a heterogeneous group of incurable motor neuron diseases (MNDs) characterized by a selective loss of upper and lower motor neurons in the brain and spinal cord. Most cases of ALS are sporadic, while approximately 5–10% cases are familial. More than 16 causative genes for ALS/MNDs have been identified and their underlying pathogenesis, including oxidative stress, endoplasmic reticulum stress, excitotoxicity, mitochondrial dysfunction, neural inflammation, protein misfolding and accumulation, dysfunctional intracellular trafficking, abnormal RNA processing, and noncell-autonomous damage, has begun to emerge. It is currently believed that a complex interplay of multiple toxicity pathways is implicated in disease onset and progression. Among such mechanisms, ones that are associated with disturbances of protein homeostasis, the ubiquitin-proteasome system and autophagy, have recently been highlighted. Although it remains to be determined whether disease-associated protein aggregates have a toxic or protective role in the pathogenesis, the formation of them results from the imbalance between generation and degradation of misfolded proteins within neuronal cells. In this paper, we focus on the autophagy-lysosomal and endocytic degradation systems and implication of their dysfunction to the pathogenesis of ALS/MNDs. The autophagy-endolysosomal pathway could be a major target for the development of therapeutic agents for ALS/MNDs.

scholarly journals Cuz1/Ynl155w, a Zinc-dependent Ubiquitin-binding Protein, Protects Cells from Metalloid-induced Proteotoxicity

2013 ◽  
Vol 289 (3) ◽  
pp. 1876-1885 ◽  
Author(s):  
John Hanna ◽  
David Waterman ◽  
Marta Isasa ◽  
Suzanne Elsasser ◽  
Yuan Shi ◽  
...  
Keyword(s):  
Stress Response ◽  
Protein Misfolding ◽  
Binding Protein ◽  
Ubiquitin Proteasome System ◽  
Cellular Stress Response ◽  
Related Protein ◽  
Ubiquitin System ◽  
Stress Response Pathway ◽  
Ubiquitin Binding ◽  
Ubiquitin Proteasome

Protein misfolding is a universal threat to cells. The ubiquitin-proteasome system mediates a cellular stress response capable of eliminating misfolded proteins. Here we identify Cuz1/Ynl155w as a component of the ubiquitin system, capable of interacting with both the proteasome and Cdc48. Cuz1/Ynl155w is regulated by the transcription factor Rpn4, and is required for cells to survive exposure to the trivalent metalloids arsenic and antimony. A related protein, Yor052c, shows similar phenotypes, suggesting a multicomponent stress response pathway. Cuz1/Ynl155w functions as a zinc-dependent ubiquitin-binding protein. Thus, Cuz1/Ynl155w is proposed to protect cells from metalloid-induced proteotoxicity by delivering ubiquitinated substrates to Cdc48 and the proteasome for destruction.

Protein misfolding and aggregation in neurodegenerative diseases: a review of pathogeneses, novel detection strategies, and potential therapeutics

2019 ◽  
Vol 30 (4) ◽  
pp. 339-358 ◽  
Author(s):  
Jason Gandhi ◽  
Anthony C. Antonelli ◽  
Adil Afridi ◽  
Sohrab Vatsia ◽  
Gunjan Joshi ◽  
...  
Keyword(s):  
Protein Folding ◽  
Neurodegenerative Diseases ◽  
Protein Misfolding ◽  
Ubiquitin Proteasome System ◽  
Transmissible Spongiform Encephalopathies ◽  
Stable Conformation ◽  
Spongiform Encephalopathies ◽  
Folding Process ◽  
Ubiquitin Proteasome ◽  
Protein Misfolding And Aggregation

Abstract Protein folding is a complex, multisystem process characterized by heavy molecular and cellular footprints. Chaperone machinery enables proper protein folding and stable conformation. Other pathways concomitant with the protein folding process include transcription, translation, post-translational modifications, degradation through the ubiquitin-proteasome system, and autophagy. As such, the folding process can go awry in several different ways. The pathogenic basis behind most neurodegenerative diseases is that the disruption of protein homeostasis (i.e. proteostasis) at any level will eventually lead to protein misfolding. Misfolded proteins often aggregate and accumulate to trigger neurotoxicity through cellular stress pathways and consequently cause neurodegenerative diseases. The manifestation of a disease is usually dependent on the specific brain region that the neurotoxicity affects. Neurodegenerative diseases are age-associated, and their incidence is expected to rise as humans continue to live longer and pursue a greater life expectancy. We presently review the sequelae of protein misfolding and aggregation, as well as the role of these phenomena in several neurodegenerative diseases including Alzheimer’s disease, Huntington’s disease, amyotrophic lateral sclerosis, Parkinson’s disease, transmissible spongiform encephalopathies, and spinocerebellar ataxia. Strategies for treatment and therapy are also conferred with respect to impairing, inhibiting, or reversing protein misfolding.

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 Nuclear Ubiquitin-Proteasome Pathways in Proteostasis Maintenance

Biomolecules ◽  
2021 ◽  
Vol 11 (1) ◽  
pp. 54
Author(s):  
Dina Franić ◽  
Klara Zubčić ◽  
Mirta Boban
Keyword(s):  
Quality Control ◽  
Protein Misfolding ◽  
Protein Quality ◽  
Protein Quality Control ◽  
Ubiquitin Proteasome System ◽  
Cytoplasmic Proteins ◽  
Ubiquitin Proteasome ◽  
A Cell ◽  
Protein Misfolding And Aggregation ◽  
Order Complexes

Protein homeostasis, or proteostasis, is crucial for the functioning of a cell, as proteins that are mislocalized, present in excessive amounts, or aberrant due to misfolding or other type of damage can be harmful. Proteostasis includes attaining the correct protein structure, localization, and the formation of higher order complexes, and well as the appropriate protein concentrations. Consequences of proteostasis imbalance are evident in a range of neurodegenerative diseases characterized by protein misfolding and aggregation, such as Alzheimer’s, Parkinson’s, and amyotrophic lateral sclerosis. To protect the cell from the accumulation of aberrant proteins, a network of protein quality control (PQC) pathways identifies the substrates and direct them towards refolding or elimination via regulated protein degradation. The main pathway for degradation of misfolded proteins is the ubiquitin-proteasome system. PQC pathways have been first described in the cytoplasm and the endoplasmic reticulum, however, accumulating evidence indicates that the nucleus is an important PQC compartment for ubiquitination and proteasomal degradation of not only nuclear, but also cytoplasmic proteins. In this review, we summarize the nuclear ubiquitin-proteasome pathways involved in proteostasis maintenance in yeast, focusing on inner nuclear membrane-associated degradation (INMAD) and San1-mediated protein quality control.

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.

Protein Quality Control Degradation in the Nucleus

2018 ◽  
Vol 87 (1) ◽  
pp. 725-749 ◽  
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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