Crosstalk between Biomolecular Condensates and Proteostasis

Amzallag, Emmanuel; Hornstein, Eran

doi:10.3390/cells11152415

Cited by 8 publications

(7 citation statements)

References 109 publications

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“…The “free” 20S CPs are nuclear even under osmotic stress, although they do not form the classical condensate granules of the 26S proteasome. It has been reported that RAD23B, a ubiquitin-binding shuttle protein, is essential in the formation of nuclear proteasomal condensates [ 21 , 33 , 36 ]. The p62/SQSTM1 ubiquitin-binding protein is another ubiquitin shuttle protein regulating nuclear condensates [ 33 , 37 ].…”

Section: Discussionmentioning

confidence: 99%

Method of Monitoring 26S Proteasome in Cells Revealed the Crucial Role of PSMA3 C-Terminus in 26S Integrity

2023

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Proteasomes critically regulate proteostasis via protein degradation. Proteasomes are multi-subunit complexes composed of the 20S proteolytic core particle (20S CP) that, in association with one or two 19S regulatory particles (19S RPs), generates the 26S proteasome, which is the major proteasomal complex in cells. Native gel protocols are used to investigate the 26S/20S ratio. However, a simple method for detecting these proteasome complexes in cells is missing. To this end, using CRISPR technology, we YFP-tagged the endogenous PSMB6 (β1) gene, a 20S CP subunit, and co-tagged endogenous PSMD6 (Rpn7), a 19S RP subunit, with the mScarlet fluorescent protein. We observed the colocalization of the YFP and mScarlet fluorescent proteins in the cells, with higher nuclear accumulation. Nuclear proteasomal granules are formed under osmotic stress, and all were positive for YFP and mScarlet. Previously, we have reported that PSMD1 knockdown, one of the 19 RP subunits, gives rise to a high level of “free” 20S CPs. Intriguingly, under this condition, the 20S-YFP remained nuclear, whereas the PSMD6-mScarlet was mostly in cytoplasm, demonstrating the distinct subcellular distribution of uncapped 20S CPs. Lately, we have shown that the PSMA3 (α7) C-terminus, a 20S CP subunit, binds multiple intrinsically disordered proteins (IDPs). Remarkably, the truncation of the PSMA3 C-terminus is phenotypically reminiscent of PSMD1 knockdown. These data suggest that the PSMA3 C-terminal region is critical for 26S proteasome integrity.

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Section: Discussionmentioning

confidence: 99%

Method of Monitoring 26S Proteasome in Cells Revealed the Crucial Role of PSMA3 C-Terminus in 26S Integrity

2023

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“…The UPS system is strongly associated with regulating biomolecular condensation ( 60 ). More specifically, ubiquitin and other post-translational modifications act as agents of phase separation, and are essential for the formation of condensates and ubiquitin-proteasome system activity ( 5 ). It is noteworthy that previous studies demonstrated that polyubiquitin chains can function as multivalent molecules that can drive either the assembly or the disassembly of condensates via interactions with various ubiquitin-binding proteins ( 72 , 73 ).…”

Section: Hypoxia-induced Protein Aggregation and Regulatory Responsesmentioning

confidence: 99%

“…However, these two types of higher-order protein assemblers are not completely independent. Disruptions in protein homeostasis under pressure or under pathological conditions can result in an imbalance of biomolecular condensation, ultimately leading to the uncontrolled collapse of these structures, which in turn triggers the irreversible aggregation and misfolding of protein constituents, and often leads to the transformation of aged or solidified condensates into aggregates ( 4 , 5 ).…”

Section: Introductionmentioning

confidence: 99%

Protein aggregation and biomolecular condensation in hypoxic environments (Review)

Li,

Hao,

Yang

et al. 2024

Int J Mol Med

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Due to molecular forces, biomacromolecules assemble into liquid condensates or solid aggregates, and their corresponding formation and dissolution processes are controlled. Protein homeostasis is disrupted by increasing age or environmental stress, leading to irreversible protein aggregation. Hypoxic pressure is an important factor in this process, and uncontrolled protein aggregation has been widely observed in hypoxia-related conditions such as neurodegenerative disease, cardiovascular disease, hypoxic brain injury and cancer. Biomolecular condensates are also high-order complexes assembled from macromolecules. Although they exist in different phase from protein aggregates, they are in dynamic balance under certain conditions, and their activation or assembly are considered as important regulatory processes in cell survival with hypoxic pressure. Therefore, a better understanding of the relationship between hypoxic stress, protein aggregation and biomolecular condensation will bring marked benefits in the clinical treatment of various diseases. The aim of the present review was to summarize the underlying mechanisms of aggregate assembly and dissolution induced by hypoxic conditions, and address recent breakthroughs in understanding the role of aggregates in hypoxic-related diseases, given the hypotheses that hypoxia induces macromolecular assemblage changes from a liquid to a solid phase, and that adenosine triphosphate depletion and ATP-driven inactivation of multiple protein chaperones play important roles among the process. Moreover, it is anticipated that an improved understanding of the adaptation in hypoxic environments could extend the overall survival of patients and provide new strategies for hypoxic-related diseases.

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“…Moreover, proteasomes and related marker proteins such as p62/SQSTM1 also recruit into LLPS. This process improves the efficiency of proteasomes and autolysosomes to clear misfolded proteins [41,42].…”

Section: Protein Aggregation Caused By Losing Of Proteostasismentioning

confidence: 99%

Cellular Protein Aggregates: Formation, Biological Effects, and Ways of Elimination

Wen

Feng

et al. 2023

IJMS

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The accumulation of protein aggregates is the hallmark of many neurodegenerative diseases. The dysregulation of protein homeostasis (or proteostasis) caused by acute proteotoxic stresses or chronic expression of mutant proteins can lead to protein aggregation. Protein aggregates can interfere with a variety of cellular biological processes and consume factors essential for maintaining proteostasis, leading to a further imbalance of proteostasis and further accumulation of protein aggregates, creating a vicious cycle that ultimately leads to aging and the progression of age-related neurodegenerative diseases. Over the long course of evolution, eukaryotic cells have evolved a variety of mechanisms to rescue or eliminate aggregated proteins. Here, we will briefly review the composition and causes of protein aggregation in mammalian cells, systematically summarize the role of protein aggregates in the organisms, and further highlight some of the clearance mechanisms of protein aggregates. Finally, we will discuss potential therapeutic strategies that target protein aggregates in the treatment of aging and age-related neurodegenerative diseases.

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Crosstalk between Biomolecular Condensates and Proteostasis

Cited by 8 publications

References 109 publications

Method of Monitoring 26S Proteasome in Cells Revealed the Crucial Role of PSMA3 C-Terminus in 26S Integrity

Method of Monitoring 26S Proteasome in Cells Revealed the Crucial Role of PSMA3 C-Terminus in 26S Integrity

Protein aggregation and biomolecular condensation in hypoxic environments (Review)

Cellular Protein Aggregates: Formation, Biological Effects, and Ways of Elimination

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