The Roles of Ubiquitin-Binding Protein Shuttles in the Degradative Fate of Ubiquitinated Proteins in the Ubiquitin-Proteasome System and Autophagy

Zientara‐Rytter, Katarzyna; Subramani, Suresh

doi:10.3390/cells8010040

Cited by 99 publications

(86 citation statements)

References 252 publications

(365 reference statements)

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“…Several proteins operate at the crossroad between UPS and autophagy to regulate the sorting and shuttling of ubiquitinated substrates towards either system. For instance, ubiquitin tagging is key in sorting protein substrates for either UPS-or autophagy-dependent degradation [84]. In this context, ubiquilin proteins (UBQLNs) bind the ubiquitin chains which are attached to a variety of aggregation-prone proteins, fostering their delivery and degradation by either UPS or autophagy [85][86][87].…”

Section: Emerging Mechanisms Underlying Autophagy and Proteasome Crosmentioning

confidence: 99%

Promiscuous Roles of Autophagy and Proteasome in Neurodegenerative Proteinopathies

Limanaqi

Biagioni

Gambardella

et al. 2020

IJMS

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Alterations in autophagy and the ubiquitin proteasome system (UPS) are commonly implicated in protein aggregation and toxicity which manifest in a number of neurological disorders. In fact, both UPS and autophagy alterations are bound to the aggregation, spreading and toxicity of the so-called prionoid proteins, including alpha synuclein (α-syn), amyloid-beta (Aβ), tau, huntingtin, superoxide dismutase-1 (SOD-1), TAR-DNA-binding protein of 43 kDa (TDP-43) and fused in sarcoma (FUS). Recent biochemical and morphological studies add to this scenario, focusing on the coordinated, either synergistic or compensatory, interplay that occurs between autophagy and the UPS. In fact, a number of biochemical pathways such as mammalian target of rapamycin (mTOR), transcription factor EB (TFEB), Bcl2-associated athanogene 1/3 (BAG3/1) and glycogen synthase kinase beta (GSk3β), which are widely explored as potential targets in neurodegenerative proteinopathies, operate at the crossroad between autophagy and UPS. These biochemical steps are key in orchestrating the specificity and magnitude of the two degradation systems for effective protein homeostasis, while intermingling with intracellular secretory/trafficking and inflammatory pathways. The findings discussed in the present manuscript are supposed to add novel viewpoints which may further enrich our insight on the complex interactions occurring between cell-clearing systems, protein misfolding and propagation. Discovering novel mechanisms enabling a cross-talk between the UPS and autophagy is expected to provide novel potential molecular targets in proteinopathies.

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Section: Emerging Mechanisms Underlying Autophagy and Proteasome Crosmentioning

confidence: 99%

Promiscuous Roles of Autophagy and Proteasome in Neurodegenerative Proteinopathies

Limanaqi

Biagioni

Gambardella

et al. 2020

IJMS

View full text Add to dashboard Cite

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“…Proteostasis is a protein homeostasis process ensuring an intracellular balance between generation of newly synthesized proteins and degradation. Degradation of misfolded proteins, oxidant-damaged proteins, and short-lived regulatory proteins requires the activity of the ubiquitin-proteasome system (UPS) (1)(2)(3). The UPS is a major degradation system in eukaryotes that breaks down its target proteins within two main steps, ubiquitination and proteolysis.…”

Section: Introductionmentioning

confidence: 99%

Molecular Insight Into the IRE1α-Mediated Type I Interferon Response Induced by Proteasome Impairment in Myeloid Cells of the Brain

et al. 2019

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Proteostasis is critical for cells to maintain the balance between protein synthesis, quality control, and degradation. This is particularly important for myeloid cells of the central nervous system as their immunological function relies on proper intracellular protein turnover by the ubiquitin-proteasome system. Accordingly, disruption of proteasome activity due to, e.g., loss-of-function mutations within genes encoding proteasome subunits, results in systemic autoinflammation. On the molecular level, pharmacological inhibition of proteasome results in endoplasmic reticulum (ER) stress-activated unfolded protein response (UPR) as well as an induction of type I interferons (IFN). Nevertheless, our understanding as to whether and to which extent UPR signaling regulates type I IFN response is limited. To address this issue, we have tested the effects of proteasome dysfunction upon treatment with proteasome inhibitors in primary murine microglia and microglia-like cell line BV-2. Our data show that proteasome impairment by bortezomib is a stimulus that activates all three intracellular ER-stress transducers activation transcription factor 6, protein kinase R-like endoplasmic reticulum kinase and inositol-requiring protein 1 alpha (IRE1α), causing a full activation of the UPR. We further demonstrate that impaired proteasome activity in microglia cells triggers an induction of IFNβ1 in an IRE1-dependent manner. An inhibition of the IRE1 endoribonuclease activity significantly attenuates TANK-binding kinase 1-mediated activation of type I IFN. Moreover, interfering with TANK-binding kinase 1 activity also compromised the expression of C/EBP homologous protein 10, thereby emphasizing a multilayered interplay between UPR and type IFN response pathway. Interestingly, the induced protein kinase R-like endoplasmic reticulum kinase-activation transcription factor 4-C/EBP homologous protein 10 and IRE1-X-box-binding protein 1 axes caused a significant upregulation of proinflammatory cytokine interleukin 6 expression that exacerbates STAT1/STAT3 signaling in cells with dysfunctional proteasomes. Altogether, these findings indicate that proteasome impairment disrupts ER homeostasis and triggers a complex interchange between ER-stress sensors and type I IFN signaling, thus inducing in myeloid cells a state of chronic inflammation.

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“…Degraded macromolecules are then transported back to the cytosol to be reused [12]. In selective autophagy, autophagy receptors such as optineurin or p62 recognise ubiquitinated proteins for degradation via their UBAN (ubiquitin-binding domain in ABIN proteins and nemo) or UBA (ubiquitin-associated) domains, respectively, and traffic them to the phagophore [13]. The autophagy receptors then bind to the autophagosomal membrane through an interaction with light chain 3 (LC3) mediated by an LC3-interacting region (LIR).…”

Section: Autophagy Processmentioning

confidence: 99%

Activate or Inhibit? Implications of Autophagy Modulation as a Therapeutic Strategy for Alzheimer’s Disease

Krishnan

Shrestha

Jayatunga

et al. 2020

IJMS

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Neurodegenerative diseases result in a range of conditions depending on the type of proteinopathy, genes affected or the location of the degeneration in the brain. Proteinopathies such as senile plaques and neurofibrillary tangles in the brain are prominent features of Alzheimer’s disease (AD). Autophagy is a highly regulated mechanism of eliminating dysfunctional organelles and proteins, and plays an important role in removing these pathogenic intracellular protein aggregates, not only in AD, but also in other neurodegenerative diseases. Activating autophagy is gaining interest as a potential therapeutic strategy for chronic diseases featuring protein aggregation and misfolding, including AD. Although autophagy activation is a promising intervention, over-activation of autophagy in neurodegenerative diseases that display impaired lysosomal clearance may accelerate pathology, suggesting that the success of any autophagy-based intervention is dependent on lysosomal clearance being functional. Additionally, the effects of autophagy activation may vary significantly depending on the physiological state of the cell, especially during proteotoxic stress and ageing. Growing evidence seems to favour a strategy of enhancing the efficacy of autophagy by preventing or reversing the impairments of the specific processes that are disrupted. Therefore, it is essential to understand the underlying causes of the autophagy defect in different neurodegenerative diseases to explore possible therapeutic approaches. This review will focus on the role of autophagy during stress and ageing, consequences that are linked to its activation and caveats in modulating this pathway as a treatment.

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The Roles of Ubiquitin-Binding Protein Shuttles in the Degradative Fate of Ubiquitinated Proteins in the Ubiquitin-Proteasome System and Autophagy

Cited by 99 publications

References 252 publications

Promiscuous Roles of Autophagy and Proteasome in Neurodegenerative Proteinopathies

Promiscuous Roles of Autophagy and Proteasome in Neurodegenerative Proteinopathies

Molecular Insight Into the IRE1α-Mediated Type I Interferon Response Induced by Proteasome Impairment in Myeloid Cells of the Brain

Activate or Inhibit? Implications of Autophagy Modulation as a Therapeutic Strategy for Alzheimer’s Disease

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