Protein quality control in the nucleolus safeguards recovery of epigenetic regulators after heat shock

Azkanaz, Maria; López, Aida Rodríguez; Boer, Bauke de; Huiting, Wouter; Angrand, Pierre‐Olivier; Vellenga, Edo; Kampinga, Harm H.; Bergink, Steven; Martens, Joost H.A.; Schuringa, Jan Jacob; Boom, Vincent van den

doi:10.7554/elife.45205

Cited by 56 publications

(56 citation statements)

References 73 publications

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“…GO analysis of PIP2-effectors further identified proteins linked to proteasome, heat response, and nucleoli localization. Heat shock induced protein aggregates or misfolded proteins are directed to nucleoli [ 42 , 43 ]. The degradation of protein aggregates is in general mediated by proteasomal or autophagy processes [ 44 , 45 , 46 ].…”

Section: Discussionmentioning

confidence: 99%

“…The degradation of protein aggregates is in general mediated by proteasomal or autophagy processes [ 44 , 45 , 46 ]. Ubiquitinated and heat shock proteins form aggresomes within the nucleolus [ 43 , 47 ] Proteins sensitive to heat shock denaturation, which are enriched for disordered regions, can be refolded within the nucleolus [ 42 ]. Nucleolar aggresomes contain proteins such as fibrillarin, ubiquitin, or autophagy factor LC3 [ 48 , 49 ].…”

Section: Discussionmentioning

confidence: 99%

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Limited Proteolysis-Coupled Mass Spectrometry Identifies Phosphatidylinositol 4,5-Bisphosphate Effectors in Human Nuclear Proteome

Sztacho

Šalovská

Cervenka

et al. 2021

Cells

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Specific nuclear sub-compartments that are regions of fundamental processes such as gene expression or DNA repair, contain phosphoinositides (PIPs). PIPs thus potentially represent signals for the localization of specific proteins into different nuclear functional domains. We performed limited proteolysis followed by label-free quantitative mass spectrometry and identified nuclear protein effectors of the most abundant PIP—phosphatidylinositol 4,5-bisphosphate (PIP2). We identified 515 proteins with PIP2-binding capacity of which 191 ‘exposed’ proteins represent a direct PIP2 interactors and 324 ‘hidden’ proteins, where PIP2 binding was increased upon trypsin treatment. Gene ontology analysis revealed that ‘exposed’ proteins are involved in the gene expression as regulators of Pol II, mRNA splicing, and cell cycle. They localize mainly to non-membrane bound organelles—nuclear speckles and nucleolus and are connected to the actin nucleoskeleton. ‘Hidden’ proteins are linked to the gene expression, RNA splicing and transport, cell cycle regulation, and response to heat or viral infection. These proteins localize to the nuclear envelope, nuclear pore complex, or chromatin. Bioinformatic analysis of peptides bound in both groups revealed that PIP2-binding motifs are in general hydrophilic. Our data provide an insight into the molecular mechanism of nuclear PIP2 protein interaction and advance the methodology applicable for further studies of PIPs or other protein ligands.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Limited Proteolysis-Coupled Mass Spectrometry Identifies Phosphatidylinositol 4,5-Bisphosphate Effectors in Human Nuclear Proteome

Sztacho

Šalovská

Cervenka

et al. 2021

Cells

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“…Recently, increasing studies have indicated that, in addition to the canonical functions of regulating ribosome biogenesis, the nucleolus also plays significant roles in protein quality control ( Frottin et al., 2019 ; Amer-Sarsour and Ashkenazi, 2019 ; Azkanaz et al., 2019 ; Rekulapally and Suresh, 2019 ) and degradation ( Song and Wu, 2005 ; Tao et al., 2013 ; Guan et al., 2016 ). For instance, Survivin-deltaEx3, a splice variant of Survivin, was reported to be degraded through the nucleolus-mediated protein degradation pathway in a ubiquitination-proteasome-dependent manner ( Song and Wu, 2005 ).…”

Section: Discussionmentioning

confidence: 99%

The nucleolus functions as the compartment for histone H2B protein degradation

Liu

Wang

et al. 2021

iScience

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Summary Histones are main components of chromatin, and the protein levels of histones significantly affect chromatin assembly. However, how histone protein levels are regulated, especially whether and how histones are degraded, is largely unclear. Here, we found that histone H2B is mainly degraded through the proteasome-mediated pathway, and the lysine-120 site of H2B is essential for its K48-linked polyubiquitination and degradation. Moreover, the degradation-impaired H2BK120R mutant shows an increased nucleolus localization, and inhibition of the proteasome results in an elevated nucleolus distribution of wild-type H2B, which is similar to that of H2BK120R mutants. More importantly, the nucleolus fractions can ubiquitinate and degrade the purified H2B in vitro , suggesting that the nucleolus, in addition to its canonical roles regulating ribosome genesis and protein translation, likely associates with H2B degradation. Therefore, these findings revealed a novel mechanism for the regulation of H2B degradation in which a nucleolus-associated proteasome pathway is involved.

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“…This correlates with the predictive scoring of stress granule-associated proteins that suggests that various protein classes are capable of phase separation in different cellular locations [ 122 ]. Further work shows a reconfiguration of the localisation of QC machinery upon heat stress with chaperones accumulating in nucleoli [ 123 ]. These observations are intriguing as the proteostasis circuits that govern cytosolic and nuclear QC require distinct signals in the UPS [ 102 ].…”

Section: Compartmentalisation and Phase Separationmentioning

confidence: 99%

It's not just a phase; ubiquitination in cytosolic protein quality control

Baker

Bernardini

2021

Biochemical Society Transactions

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The accumulation of misfolded proteins is associated with numerous degenerative conditions, cancers and genetic diseases. These pathological imbalances in protein homeostasis (termed proteostasis), result from the improper triage and disposal of damaged and defective proteins from the cell. The ubiquitin-proteasome system is a key pathway for the molecular control of misfolded cytosolic proteins, co-opting a cascade of ubiquitin ligases to direct terminally damaged proteins to the proteasome via modification with chains of the small protein, ubiquitin. Despite the evidence for ubiquitination in this critical pathway, the precise complement of ubiquitin ligases and deubiquitinases that modulate this process remains under investigation. Whilst chaperones act as the first line of defence against protein misfolding, the ubiquitination machinery has a pivotal role in targeting terminally defunct cytosolic proteins for destruction. Recent work points to a complex assemblage of chaperones, ubiquitination machinery and subcellular quarantine as components of the cellular arsenal against proteinopathies. In this review, we examine the contribution of these pathways and cellular compartments to the maintenance of the cytosolic proteome. Here we will particularly focus on the ubiquitin code and the critical enzymes which regulate misfolded proteins in the cytosol, the molecular point of origin for many neurodegenerative and genetic diseases.

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Protein quality control in the nucleolus safeguards recovery of epigenetic regulators after heat shock

Cited by 56 publications

References 73 publications

Limited Proteolysis-Coupled Mass Spectrometry Identifies Phosphatidylinositol 4,5-Bisphosphate Effectors in Human Nuclear Proteome

Limited Proteolysis-Coupled Mass Spectrometry Identifies Phosphatidylinositol 4,5-Bisphosphate Effectors in Human Nuclear Proteome

The nucleolus functions as the compartment for histone H2B protein degradation

It's not just a phase; ubiquitination in cytosolic protein quality control

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