scholarly journals Protein Aggregation in the Cell Nucleus: Structure, Function and Topology

2009 ◽  
Vol 2 (1) ◽  
pp. 193-199 ◽  
Author(s):  
Anna von Mikecz
Keyword(s):  
Protein Aggregation ◽  
Control Unit ◽  
Ubiquitin Proteasome System ◽  
Nuclear Bodies ◽  
Dna And Rna ◽  
Ribonucleoprotein Complexes ◽  
Ubiquitin Proteasome ◽  
Nucleus Structure ◽  
Cellular Control ◽  
Nuclear Processes

The nucleus represents a cellular control unit that regulates all events concerning the storage and processing of DNA and RNA. It is organized by highly crowded, dynamic assemblies of proteins and nucleic acids in molecular machines, ribonucleoprotein complexes, clusters of ongoing nuclear processes, nuclear bodies, and chromatin. This review discusses the occurrence of nuclear protein aggregation with special emphasis on the functional architecture of the nucleus, and quality control by the ubiquitin-proteasome system.

scholarly journals Generalizable Compositional Features Influencing the Proteostatic Fates of Polar Low-Complexity Domains

2021 ◽  
Vol 22 (16) ◽  
pp. 8944
Author(s):  
Sean M. Cascarina ◽  
Joshua P. Kaplan ◽  
Mikaela R. Elder ◽  
Lindsey Brookbank ◽  
Eric D. Ross
Keyword(s):  
Protein Aggregation ◽  
Ubiquitin Proteasome System ◽  
Low Complexity ◽  
Hydrophobic Residues ◽  
System A ◽  
Polar Low ◽  
Eukaryotic Proteomes ◽  
Ubiquitin Proteasome ◽  
Folded Proteins ◽  
Aggregation Activity

Protein aggregation is associated with a growing list of human diseases. A substantial fraction of proteins in eukaryotic proteomes constitutes a proteostasis network—a collection of proteins that work together to maintain properly folded proteins. One of the overarching functions of the proteostasis network is the prevention or reversal of protein aggregation. How proteins aggregate in spite of the anti-aggregation activity of the proteostasis machinery is incompletely understood. Exposed hydrophobic patches can trigger degradation by the ubiquitin-proteasome system, a key branch of the proteostasis network. However, in a recent study, we found that model glycine (G)-rich or glutamine/asparagine (Q/N)-rich prion-like domains differ in their susceptibility to detection and degradation by this system. Here, we expand upon this work by examining whether the features controlling the degradation of our model prion-like domains generalize broadly to G-rich and Q/N-rich domains. Experimentally, native yeast G-rich domains in isolation are sensitive to the degradation-promoting effects of hydrophobic residues, whereas native Q/N-rich domains completely resist these effects and tend to aggregate instead. Bioinformatic analyses indicate that native G-rich domains from yeast and humans tend to avoid degradation-promoting features, suggesting that the proteostasis network may act as a form of selection at the molecular level that constrains the sequence space accessible to G-rich domains. However, the sensitivity or resistance of G-rich and Q/N-rich domains, respectively, was not always preserved in their native protein contexts, highlighting that proteins can evolve other sequence features to overcome the intrinsic sensitivity of some LCDs to degradation.

scholarly journals NEDDylation promotes nuclear protein aggregation and protects the Ubiquitin Proteasome System upon proteotoxic stress

2018 ◽  
Vol 9 (1) ◽  
Author(s):  
Chantal M. Maghames ◽  
Sofia Lobato-Gil ◽  
Aurelien Perrin ◽  
Helene Trauchessec ◽  
Manuel S. Rodriguez ◽  
...  
Keyword(s):  
Protein Aggregation ◽  
Nuclear Protein ◽  
Ubiquitin Proteasome System ◽  
Proteotoxic Stress ◽  
Ubiquitin Proteasome

scholarly journals PML clastosomes prevent nuclear accumulation of mutant ataxin-7 and other polyglutamine proteins

2006 ◽  
Vol 174 (1) ◽  
pp. 65-76 ◽  
Author(s):  
Alexandre Janer ◽  
Elodie Martin ◽  
Marie-Paule Muriel ◽  
Morwena Latouche ◽  
Hiroto Fujigasaki ◽  
...  
Keyword(s):  
Ubiquitin Proteasome System ◽  
Nuclear Bodies ◽  
Nuclear Accumulation ◽  
Spinocerebellar Ataxia Type ◽  
Aggregate Formation ◽  
Potential Therapeutic Target ◽  
Promyelocytic Leukemia Protein ◽  
Pml Nuclear Bodies ◽  
Spinocerebellar Ataxia Type 7 ◽  
Ubiquitin Proteasome

The pathogenesis of spinocerebellar ataxia type 7 and other neurodegenerative polyglutamine (polyQ) disorders correlates with the aberrant accumulation of toxic polyQ-expanded proteins in the nucleus. Promyelocytic leukemia protein (PML) nuclear bodies are often present in polyQ aggregates, but their relation to pathogenesis is unclear. We show that expression of PML isoform IV leads to the formation of distinct nuclear bodies enriched in components of the ubiquitin-proteasome system. These bodies recruit soluble mutant ataxin-7 and promote its degradation by proteasome-dependent proteolysis, thus preventing the aggregate formation. Inversely, disruption of the endogenous nuclear bodies with cadmium increases the nuclear accumulation and aggregation of mutant ataxin-7, demonstrating their role in ataxin-7 turnover. Interestingly, β-interferon treatment, which induces the expression of endogenous PML IV, prevents the accumulation of transiently expressed mutant ataxin-7 without affecting the level of the endogenous wild-type protein. Therefore, clastosomes represent a potential therapeutic target for preventing polyQ disorders.

scholarly journals The p97-UBXN1 complex regulates aggresome formation

2020 ◽  
Author(s):  
Sirisha Mukkavalli ◽  
Jacob Aaron Klickstein ◽  
Betty Ortiz ◽  
Peter Juo ◽  
Malavika Raman
Keyword(s):  
Protein Aggregation ◽  
Mammalian Cells ◽  
Proteasome Inhibition ◽  
Adaptor Proteins ◽  
Ubiquitin Proteasome System ◽  
Aaa Atpase ◽  
Evolutionarily Conserved ◽  
Ubiquitin Proteasome ◽  
Aggresome Formation

AbstractThe recognition and disposal of misfolded proteins are essential for the maintenance of cellular homeostasis. Perturbations in the pathways that promote degradation of aberrant proteins contribute to a variety of protein aggregation disorders broadly termed proteinopathies. It is presently unclear how diverse disease-relevant aggregates are recognized and processed for degradation. The p97 AAA-ATPase in combination with a host of adaptor proteins functions to identify ubiquitylated proteins and target them for degradation by the ubiquitin-proteasome system or through autophagy. Mutations in p97 cause multi-system proteinopathies; however, the precise defects underlying these disorders are unclear given the large number of pathways that rely on p97 function. Here, we systematically investigate the role of p97 and its adaptors in the process of formation of aggresomes which are membrane-less structures containing ubiquitylated proteins that arise upon proteasome inhibition. We demonstrate that p97 mediates both aggresome formation and clearance in proteasome-inhibited cells. We identify a novel and specific role for the p97 adaptor UBXN1 in the process of aggresome formation. UBXN1 is recruited to ubiquitin-positive aggresomes and UBXN1 knockout cells are unable to form a single aggresome, and instead display dispersed ubiquitin aggregates. Furthermore, loss of p97-UBXN1 results in the increase in Huntingtin polyQ aggregates both in mammalian cells as well as in a C.elegans model of Huntington’s Disease. Together our work identifies evolutionarily conserved roles for p97 and its adaptor UBXN1 in the disposal of protein aggregates.

scholarly journals Gammaherpesviral Tegument Proteins, PML-Nuclear Bodies and the Ubiquitin-Proteasome System

Viruses ◽  
2017 ◽  
Vol 9 (10) ◽  
pp. 308 ◽  
Author(s):  
Florian Full ◽  
Alexander Hahn ◽  
Anna Großkopf ◽  
Armin Ensser
Keyword(s):  
Ubiquitin Proteasome System ◽  
Nuclear Bodies ◽  
Tegument Proteins ◽  
Pml Nuclear Bodies ◽  
Ubiquitin Proteasome

scholarly journals Ube2v1 Positively Regulates Protein Aggregation by Modulating Ubiquitin Proteasome System Performance Partially Through K63 Ubiquitination

2020 ◽  
Vol 126 (7) ◽  
pp. 907-922 ◽  
Author(s):  
Na Xu ◽  
James Gulick ◽  
Hanna Osinska ◽  
Yang Yu ◽  
Patrick M. McLendon ◽  
...  
Keyword(s):  
Protein Aggregation ◽  
System Performance ◽  
Ubiquitin Proteasome System ◽  
Neonatal Rat ◽  
Autophagic Flux ◽  
Aggregate Formation ◽  
Protein Aggregate ◽  
Ventricular Cardiomyocytes ◽  
A Genome ◽  
Ubiquitin Proteasome

Rationale: Compromised protein quality control can result in proteotoxic intracellular protein aggregates in the heart, leading to cardiac disease and heart failure. Defining the participants and understanding the underlying mechanisms of cardiac protein aggregation is critical for seeking therapeutic targets. We identified Ube2v1 (ubiquitin-conjugating enzyme E2 variant 1) in a genome-wide screen designed to identify novel effectors of the aggregation process. However, its role in the cardiomyocyte is undefined. Objective: To assess whether Ube2v1 regulates the protein aggregation caused by cardiomyocyte expression of a mutant αB crystallin (CryAB R120G ) and identify how Ube2v1 exerts its effect. Methods and Results: Neonatal rat ventricular cardiomyocytes were infected with adenoviruses expressing either wild-type CryAB (CryAB WT ) or CryAB R120G . Subsequently, loss- and gain-of-function experiments were performed. Ube2v1 knockdown decreased aggregate accumulation caused by CryAB R120G expression. Overexpressing Ube2v1 promoted aggregate formation in CryAB WT and CryAB R120G -expressing neonatal rat ventricular cardiomyocytes. Ubiquitin proteasome system performance was analyzed using a ubiquitin proteasome system reporter protein. Ube2v1 knockdown improved ubiquitin proteasome system performance and promoted the degradation of insoluble ubiquitinated proteins in CryAB R120G cardiomyocytes but did not alter autophagic flux. Lys (K) 63-linked ubiquitination modulated by Ube2v1 expression enhanced protein aggregation and contributed to Ube2v1’s function in regulating protein aggregate formation. Knocking out Ube2v1 exclusively in cardiomyocytes by using AAV9 (adeno-associated virus 9) to deliver multiplexed single guide RNAs against Ube2v1 in cardiac-specific Cas9 mice alleviated CryAB R120G -induced protein aggregation, improved cardiac function, and prolonged lifespan in vivo. Conclusions: Ube2v1 plays an important role in protein aggregate formation, partially by enhancing K63 ubiquitination during a proteotoxic stimulus. Inhibition of Ube2v1 decreases CryAB R120G -induced aggregate formation through enhanced ubiquitin proteasome system performance rather than autophagy and may provide a novel therapeutic target to treat cardiac proteinopathies.

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