Chaperone-Mediated Protein Disaggregation Triggers Proteolytic Clearance of Intra-nuclear Protein Inclusions

Brave, Fabian den; Cairo, Lucas V.; Jagadeesan, Chandhuru; Ruger-Herreros, Carmen; Mogk, Axel; Bukau, Bernd; Jentsch, Stefan

doi:10.1016/j.celrep.2020.107680

Cited by 55 publications

(51 citation statements)

References 67 publications

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“…The involvement of the Hsp40 co-chaperone in the proteasome-dependent disaggregation of transient-QC is in line with findings that established Hsp40 co-chaperones not only as Hsp70 activators but also as regulators of their binding specificity and functional diversity [32][33][34][35]. Now, the den Brave study, not only establishes the function of the nuclear Hsp40, Apj1, in INQ clearance, but it also indicates that Hsp104-dependent refolding and proteasome-mediated degradation of solubilized misfolded proteins are independent disaggregation triage reactions [32]. Yet, Hsp104 activity is required for the turnover of aggregation-prone, membrane-embedded, Endoplasmic Reticulum-Associated Degradation (ERAD) substrates, but not for their soluble counterparts [36].…”

Section: Misfolded Proteins Are Extracted From Cell Inclusions and Sosupporting

confidence: 87%

“…A recent study from the late Stephan Jentsch lab [31] has demonstrated that the yeast Hsp70/Apj1 bi-chaperone pair, in cooperation with Hsp110, exclusively couples the dissolution of INQ to 26S proteasome-mediated degradation, independently of Hsp104 function [32]. The involvement of the Hsp40 co-chaperone in the proteasome-dependent disaggregation of transient-QC is in line with findings that established Hsp40 co-chaperones not only as Hsp70 activators but also as regulators of their binding specificity and functional diversity [32][33][34][35]. Now, the den Brave study, not only establishes the function of the nuclear Hsp40, Apj1, in INQ clearance, but it also indicates that Hsp104-dependent refolding and proteasome-mediated degradation of solubilized misfolded proteins are independent disaggregation triage reactions [32].…”

Section: Misfolded Proteins Are Extracted From Cell Inclusions and Somentioning

confidence: 99%

“…The findings that overexpression of mutant CFTR or inhibition of the proteasome in cultured mammalian cells results in aggresomes formation [3,37], led to the understanding that proteasomes play a key role in the dynamics of protein inclusion bodies. Yet, it was only when the dynamics of pre-formed protein inclusions in yeast had been investigated under conditions where new protein synthesis is curtailed, that a key role of proteasomes in transient-QC clearance was realized [8,32,38].…”

Section: A Role Of the Ubiquitin-proteasome System In Protein Qualitymentioning

confidence: 99%

“…While the essential role of the proteasome in transient-QC disaggregation has been established [8,18,32], one should take into account that these studies often follow the fate of proteins that are beyond refolding and invariably degraded by the proteasome. Therefore, in each case, aggregate dissolution depends on proteasome activity.…”

Section: Proteasome Inhibition Induces Transient-qc Accumulationmentioning

confidence: 99%

“…The elimination of transient-QC bodies entails preliminary solubilization of monomers, only after which, the liberated misfolded proteins are subjected to proteasomal degradation [32,38,45,46]. Understanding how solubilized misfolded proteins that fail to refold are targeted to the proteasome is key to elucidating the operation of the PQC network in health and disease.…”

Section: Ubqln2 Bridges Between Transient-qc Bodies and The 26s Protementioning

confidence: 99%

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Releasing the Lockdown: An Emerging Role for the Ubiquitin-Proteasome System in the Breakdown of Transient Protein Inclusions

2020

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Intracellular protein inclusions are diverse cellular entities with distinct biological properties. They vary in their protein content, sequestration sites, physiological function, conditions for their generation, and turnover rates. Major distinctions have been recognized between stationary amyloids and dynamic, misfolded protein deposits. The former being a dead end for irreversibly misfolded proteins, hence, cleared predominantly by autophagy, while the latter consists of a protein-quality control mechanism, important for cell endurance, where proteins are sequestered during proteotoxic stress and resolved upon its relief. Accordingly, the disaggregation of transient inclusions is a regulated process consisting of protein solubilization, followed by a triage step to either refolding or to ubiquitin-mediated degradation. Recent studies have demonstrated an indispensable role in disaggregation for components of the chaperone and the ubiquitin–proteasome systems. These include heat-shock chaperones of the 40/70/100 kDa families, the proteasome, proteasome substrate shuttling factors, and deubiquitylating enzymes. Thus, a functional link has been established between the chaperone machinery that extracts proteins from transient deposits and 26S proteasome-dependent disaggregation, indicative of a coordinated process. In this review, we discuss data emanating from these important studies and subsequently consolidate the information in the form of a working model for the disaggregation mechanism.

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Section: Misfolded Proteins Are Extracted From Cell Inclusions and Sosupporting

confidence: 87%

Section: Misfolded Proteins Are Extracted From Cell Inclusions and Somentioning

confidence: 99%

Section: A Role Of the Ubiquitin-proteasome System In Protein Qualitymentioning

confidence: 99%

Section: Proteasome Inhibition Induces Transient-qc Accumulationmentioning

confidence: 99%

Section: Ubqln2 Bridges Between Transient-qc Bodies and The 26s Protementioning

confidence: 99%

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Releasing the Lockdown: An Emerging Role for the Ubiquitin-Proteasome System in the Breakdown of Transient Protein Inclusions

2020

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Yeast chaperones and ubiquitin ligases contribute to proteostasis during arsenite stress by preventing or clearing protein aggregates

et al. 2023

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Arsenite causes proteotoxicity by targeting nascent proteins for misfolding and aggregation. Here, we assessed how selected yeast chaperones and ubiquitin ligases contribute to proteostasis during arsenite stress. Loss of the ribosome‐associated chaperones Zuo1, Ssz1, and Ssb1/Ssb2 reduced global translation and protein aggregation, and increased arsenite resistance. Loss of cytosolic GimC/prefoldin function led to defective aggregate clearance and arsenite sensitivity. Arsenite did not induce ribosomal stalling or impair ribosome quality control, and ribosome‐associated ubiquitin ligases contributed little to proteostasis. Instead, the cytosolic ubiquitin ligase Rsp5 was important for aggregate clearance and resistance. Our study suggests that damage prevention, by decreased aggregate formation, and damage elimination, by enhanced aggregate clearance, are important protective mechanisms that maintain proteostasis during arsenite stress.

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The role of the proteasome in mitochondrial protein quality control

Rödl

Herrmann

2023

IUBMB Life

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The abundance of each cellular protein is dynamically adjusted to the prevailing metabolic and stress conditions by modulation of their synthesis and degradation rates. The proteasome represents the major machinery for the degradation of proteins in eukaryotic cells. How the ubiquitin‐proteasome system (UPS) controls protein levels and removes superfluous and damaged proteins from the cytosol and the nucleus is well characterized. However, recent studies showed that the proteasome also plays a crucial role in mitochondrial protein quality control. This mitochondria‐associated degradation (MAD) thereby acts on two layers: first, the proteasome removes mature, functionally compromised or mis‐localized proteins from the mitochondrial surface; and second, the proteasome cleanses the mitochondrial import pore of import intermediates of nascent proteins that are stalled during translocation. In this review, we provide an overview about the components and their specific functions that facilitate proteasomal degradation of mitochondrial proteins in the yeast Saccharomyces cerevisiae. Thereby we explain how the proteasome, in conjunction with a set of intramitochondrial proteases, maintains mitochondrial protein homeostasis and dynamically adapts the levels of mitochondrial proteins to specific conditions.

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Chaperone-Mediated Protein Disaggregation Triggers Proteolytic Clearance of Intra-nuclear Protein Inclusions

Cited by 55 publications

References 67 publications

Releasing the Lockdown: An Emerging Role for the Ubiquitin-Proteasome System in the Breakdown of Transient Protein Inclusions

Releasing the Lockdown: An Emerging Role for the Ubiquitin-Proteasome System in the Breakdown of Transient Protein Inclusions

Yeast chaperones and ubiquitin ligases contribute to proteostasis during arsenite stress by preventing or clearing protein aggregates

The role of the proteasome in mitochondrial protein quality control

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