Alternative systems for misfolded protein clearance: life beyond the proteasome

Johnston, Harvey E.; Samant, Rahul S.

doi:10.1111/febs.15617

Cited by 66 publications

(53 citation statements)

References 206 publications

(306 reference statements)

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“…By contrast, the larger ubiquitin-and SQSTM1-positive inclusions were also positive for LC3-II (Figure 5B, white). Furthermore, we observed that the aggregates were dispersed throughout the cytosol of Cd-treated cells, in sharp contrast to juxtanuclear aggresomes reported for misfolded proteins [65]. Similarly, Cd led to disruption of the mitochondrial network (labeled with MitoTracker dye, magenta), which was concentrated at the site of SQSTM1 aggregates (Figure 6A,B, blue), consistent with the fact that SQSTM1 is an autophagy receptor for mitochondria.…”

Section: Inhibition Of the Degradation Of Three Selective Autophagy Substrates-sqstm1 Ubiquitinated Proteins And Mitochondria By CDsupporting

confidence: 74%

The Carcinogen Cadmium Activates Lysine 63 (K63)-Linked Ubiquitin-Dependent Signaling and Inhibits Selective Autophagy

Chargui

Belaïd

Ndiaye

et al. 2021

Cancers

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Signaling, proliferation, and inflammation are dependent on K63-linked ubiquitination—conjugation of a chain of ubiquitin molecules linked via lysine 63. However, very little information is currently available about how K63-linked ubiquitination is subverted in cancer. The present study provides, for the first time, evidence that cadmium (Cd), a widespread environmental carcinogen, is a potent activator of K63-linked ubiquitination, independently of oxidative damage, activation of ubiquitin ligase, or proteasome impairment. We show that Cd induces the formation of protein aggregates that sequester and inactivate cylindromatosis (CYLD) and selective autophagy, two tumor suppressors that deubiquitinate and degrade K63-ubiquitinated proteins, respectively. The aggregates are constituted of substrates of selective autophagy—SQSTM1, K63-ubiquitinated proteins, and mitochondria. These protein aggregates also cluster double-membrane remnants, which suggests an impairment in autophagosome maturation. However, failure to eliminate these selective cargos is not due to alterations in the general autophagy process, as degradation of long-lived proteins occurs normally. We propose that the simultaneous disruption of CYLD and selective autophagy by Cd feeds a vicious cycle that further amplifies K63-linked ubiquitination and downstream activation of the NF-κB pathway, processes that support cancer progression. These novel findings link together impairment of selective autophagy, K63-linked ubiquitination, and carcinogenesis.

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Section: Inhibition Of the Degradation Of Three Selective Autophagy Substrates-sqstm1 Ubiquitinated Proteins And Mitochondria By CDsupporting

confidence: 74%

The Carcinogen Cadmium Activates Lysine 63 (K63)-Linked Ubiquitin-Dependent Signaling and Inhibits Selective Autophagy

Chargui

Belaïd

Ndiaye

et al. 2021

Cancers

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“…The cytosol is a prominent location for the subcellular quarantine of misfolded proteins. Numerous QC compartments have been described in yeast and mammals including the juxta-nuclear QC compartment (JUNQ) and insoluble protein deposit (IPOD) as well as the intranuclear QC compartment (INQ), stress granules, Q-bodies, p62 bodies and aggresome-like induced structures (reviewed in [ 104 ] and [ 105 ]). These compartments are by no means static as there is evidence of protein exchange between JUNQ and INQ [ 106 ], instead they act as molecular intersections with chaperones, UPS components and the autophagy machinery all converging here to triage damaged proteins.…”

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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“…The K48-linked polyubiquitin chain delivers target substrates to the proteasome, where ubiquitinated target substrates are degraded in an ATP-dependent manner [61,62]. In contrast, the K63-linked polyubiquitin chain is largely involved in non-proteolytic functions, such as DNA damage repair, cellular signaling, aggresome formation, and ribosome biogenesis [63][64][65][66].…”

Section: The Ubiquitin-proteasome Systemmentioning

confidence: 99%

UPF1: From mRNA Surveillance to Protein Quality Control

2021

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Selective recognition and removal of faulty transcripts and misfolded polypeptides are crucial for cell viability. In eukaryotic cells, nonsense-mediated mRNA decay (NMD) constitutes an mRNA surveillance pathway for sensing and degrading aberrant transcripts harboring premature termination codons (PTCs). NMD functions also as a post-transcriptional gene regulatory mechanism by downregulating naturally occurring mRNAs. As NMD is activated only after a ribosome reaches a PTC, PTC-containing mRNAs inevitably produce truncated and potentially misfolded polypeptides as byproducts. To cope with the emergence of misfolded polypeptides, eukaryotic cells have evolved sophisticated mechanisms such as chaperone-mediated protein refolding, rapid degradation of misfolded polypeptides through the ubiquitin–proteasome system, and sequestration of misfolded polypeptides to the aggresome for autophagy-mediated degradation. In this review, we discuss how UPF1, a key NMD factor, contributes to the selective removal of faulty transcripts via NMD at the molecular level. We then highlight recent advances on UPF1-mediated communication between mRNA surveillance and protein quality control.

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Alternative systems for misfolded protein clearance: life beyond the proteasome

Cited by 66 publications

References 206 publications

The Carcinogen Cadmium Activates Lysine 63 (K63)-Linked Ubiquitin-Dependent Signaling and Inhibits Selective Autophagy

The Carcinogen Cadmium Activates Lysine 63 (K63)-Linked Ubiquitin-Dependent Signaling and Inhibits Selective Autophagy

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

UPF1: From mRNA Surveillance to Protein Quality Control

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