Protein quality control by the proteasome and autophagy: A regulatory role of ubiquitin and liquid-liquid phase separation

Lei, Linlin; Wu, Zhixiao; Winklhofer, Konstanze F.

doi:10.1016/j.matbio.2020.11.003

Cited by 20 publications

(14 citation statements)

References 155 publications

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“…The role of PQC in protein folding is well known; however, its participation in controlling the integrity and evolution of condensates is much less understood and the focus of intense scrutiny. Indeed, condensates are an integral part of PQC, since liquid phase separation allows its spatiotemporal regulation ( Forman-Kay et al., 2018 ; Lei et al., 2021 ; Alberti and Hyman, 2021 ; Koopman et al., 2022 ).…”

Section: Promising Trends In Biomolecular Condensationmentioning

confidence: 99%

Protein conformation and biomolecular condensates

Vazquez

Toledo

Gianotti

et al. 2022

Current Research in Structural Biology

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Section: Promising Trends In Biomolecular Condensationmentioning

confidence: 99%

Protein conformation and biomolecular condensates

Vazquez

Toledo

Gianotti

et al. 2022

Current Research in Structural Biology

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“…Such mechanism has been shown to drive the self‐assembly of various other disease‐associated proteins on the pathway to the formation of solid aggregates. This phenomenon has, for example, been observed for FUS and TDP‐43 in amyotrophic lateral sclerosis and frontotemporal dementia, for tau in Alzheimer's disease, for IAPP in diabetes mellitus type II, and for PrP in prion diseases [14–24] …”

Section: Introductionmentioning

confidence: 78%

“…This phenomenon has, for example, been observed for FUS and TDP‐43 in amyotrophic lateral sclerosis and frontotemporal dementia, for tau in Alzheimer's disease, for IAPP in diabetes mellitus type II, and for PrP in prion diseases. [ 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 ]…”

Section: Introductionmentioning

confidence: 99%

Remodeling of the Fibrillation Pathway of α‐Synuclein by Interaction with Antimicrobial Peptide LL‐III

Oliva

Mukherjee

Ostermeier

et al. 2021

Chemistry A European J

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Liquid‐liquid phase separation (LLPS) has emerged as a key mechanism for intracellular organization, and many recent studies have provided important insights into the role of LLPS in cell biology. There is also evidence that LLPS is associated with a variety of medical conditions, including neurodegenerative disorders. Pathological aggregation of α‐synuclein, which is causally linked to Parkinson's disease, can proceed via droplet condensation, which then gradually transitions to the amyloid state. We show that the antimicrobial peptide LL‐III is able to interact with both monomers and condensates of α‐synuclein, leading to stabilization of the droplet and preventing conversion to the fibrillar state. The anti‐aggregation activity of LL‐III was also confirmed in a cellular model. We anticipate that studying the interaction of antimicrobial‐type peptides with liquid condensates such as α‐synuclein will contribute to the understanding of disease mechanisms (that arise in such condensates) and may also open up exciting new avenues for intervention.

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“…Defective dynamics of SGs, their persistence and transition into aggregates have been linked to neurodegenerative diseases, such as ALS and FTD. Notably, mutations in several ubiquitin-binding proteins, such as p62/SQSTM1, UBQLN2, OPTN, and VCP/p97 cause neurodegeneration, underpinning the role of ubiquitin in proteostasis regulation ( Pohl and Dikic, 2019 ; Lei et al, 2021 ). Both p62 and UBQLN2 form phase-separated condensates under different stress conditions that are regulated by ubiquitin.…”

Section: Specific Stress Granule Proteins and Their Regulation By Ubi...mentioning

confidence: 99%

“…In support of this notion, several proteins of the ubiquitination machinery are SG components ( Jain et al, 2016 ; Markmiller et al, 2018 ; Marmor-Kollet et al, 2020 ). Moreover, mutations of some of these SG components are linked to neurodegenerative diseases that are characterized by defective SG dynamics and the accumulation of polyubiquitinated protein aggregates ( Shin and Brangwynne, 2017 ; Alberti and Dormann, 2019 ; Nedelsky and Taylor, 2019 ; Mathieu et al, 2020 ; Zbinden et al, 2020 ; Lei et al, 2021 ). Pathological mutations in SG-related RBPs can also influence the SG proteome.…”

Section: Introductionmentioning

confidence: 99%

The Role of Ubiquitin in Regulating Stress Granule Dynamics

2022

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Stress granules (SGs) are dynamic, reversible biomolecular condensates, which assemble in the cytoplasm of eukaryotic cells under various stress conditions. Formation of SGs typically occurs upon stress-induced translational arrest and polysome disassembly. The increase in cytoplasmic mRNAs triggers the formation of a protein-RNA network that undergoes liquid-liquid phase separation when a critical interaction threshold has been reached. This adaptive stress response allows a transient shutdown of several cellular processes until the stress is removed. During the recovery from stress, SGs disassemble to re-establish cellular activities. Persistent stress and disease-related mutations in SG components favor the formation of aberrant SGs that are impaired in disassembly and prone to aggregation. Recently, posttranslational modifications of SG components have been identified as major regulators of SG dynamics. Here, we summarize new insights into the role of ubiquitination in affecting SG dynamics and clearance and discuss implications for neurodegenerative diseases linked to aberrant SG formation.

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Protein quality control by the proteasome and autophagy: A regulatory role of ubiquitin and liquid-liquid phase separation

Cited by 20 publications

References 155 publications

Protein conformation and biomolecular condensates

Protein conformation and biomolecular condensates

Remodeling of the Fibrillation Pathway of α‐Synuclein by Interaction with Antimicrobial Peptide LL‐III

The Role of Ubiquitin in Regulating Stress Granule Dynamics

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