Targeting the 26S Proteasome To Protect Against Proteotoxic Diseases

Myeku, Natura; Duff, Karen

doi:10.1016/j.molmed.2017.11.006

Cited by 43 publications

(42 citation statements)

References 102 publications

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“…The transcriptional/translational ER stress responses [ 42 ], as well as the pathways delivering misfolded polypeptides from the ER to the cytosol for degradation by the ubiquitin proteasome system [ 43 ], have been elucidated in molecular details. Pharmacologic modulation of the UPR [ 44 – 46 ] and the ubiquitin proteasome system [ 47 ] are expected to affect on protein misfolding diseases, cognitive disorders and tumors to mention just a few pathologic states resulting from proteostasis impairment. In sharp contrast, only recently the characterization of the molecular mechanisms ensuring lysosomal clearance of ER fragments or subdomains has attracted the interest of cell biologists.…”

Section: Discussionmentioning

confidence: 99%

Eat it right: ER-phagy and recovER-phagy

Loi

Fregno

Guerra³

et al. 2018

Biochemical Society Transactions

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The endoplasmic reticulum (ER) is the site of protein, lipid, phospholipid, steroid and oligosaccharide synthesis and modification, calcium ion storage, and detoxification of endogenous and exogenous products. Its volume (and activity) must be maintained under normal growth conditions, must be expanded in a controlled manner on activation of ER stress programs and must be reduced to pre-stress size during the recovery phase that follows ER stress termination. ER-phagy is the constitutive or regulated fragmentation and delivery of ER fragments to lysosomal compartments for clearance. It gives essential contribution to the maintenance of cellular homeostasis, proteostasis, lipidostasis and oligosaccharidostasis (i.e. the capacity to produce the proteome, lipidome and oligosaccharidome in appropriate quality and quantity). ER turnover is activated on ER stress, nutrient deprivation, accumulation of misfolded polypeptides, pathogen attack and by activators of macroautophagy. The selectivity of these poorly characterized catabolic pathways is ensured by proteins displayed at the limiting membrane of the ER subdomain to be removed from cells. These proteins are defined as ER-phagy receptors and engage the cytosolic macroautophagy machinery via specific modules that associate with ubiquitin-like, cytosolic proteins of the Atg8/LC3/GABARAP family. In this review, we give an overview on selective ER turnover and on the yeast and mammalian ER-phagy receptors identified so far.

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Section: Discussionmentioning

confidence: 99%

Eat it right: ER-phagy and recovER-phagy

Loi

Fregno

Guerra³

et al. 2018

Biochemical Society Transactions

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“…Dysregulations of the UP characterize a variety of neurological disorders where immune alterations occur, such Multiple Sclerosis (MS) and neuro-infectious diseases, but also classic neurodegenerative disorders such as Parkinson's, Alzheimer's, and Huntingtin's diseases (PD, AD, HD), epilepsy, brain stroke, and drug abuse (33–42). As such, the contribute of UP in the context of inflammatory- and immune-related biology of CNS disorders has been increasingly investigated (43, 44). The present mini-review analyzes those UP-related molecular mechanisms underpinning the shift from baseline neuro-immune surveillance to inflammatory and auto-immune neuropathology.…”

Section: Introductionmentioning

confidence: 99%

A Sentinel in the Crosstalk Between the Nervous and Immune System: The (Immuno)-Proteasome

et al. 2019

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The wealth of recent evidence about a bi-directional communication between nerve- and immune- cells revolutionized the traditional concept about the brain as an “immune-privileged” organ while opening novel avenues in the pathophysiology of CNS disorders. In fact, altered communication between the immune and nervous system is emerging as a common hallmark in neuro-developmental, neurodegenerative, and neuro-immunological diseases. At molecular level, the ubiquitin proteasome machinery operates as a sentinel at the crossroad between the immune system and brain. In fact, the standard proteasome and its alternative/inducible counterpart, the immunoproteasome, operate dynamically and coordinately in both nerve- and immune- cells to modulate neurotransmission, oxidative/inflammatory stress response, and immunity. When dysregulations of the proteasome system occur, altered amounts of standard- vs. immune-proteasome subtypes translate into altered communication between neurons, glia, and immune cells. This contributes to neuro-inflammatory pathology in a variety of neurological disorders encompassing Parkinson's, Alzheimer's, and Huntingtin's diseases, brain trauma, epilepsy, and Multiple Sclerosis. In the present review, we analyze those proteasome-dependent molecular interactions which sustain communication between neurons, glia, and brain circulating T-lymphocytes both in baseline and pathological conditions. The evidence here discussed converges in that upregulation of immunoproteasome to the detriment of the standard proteasome, is commonly implicated in the inflammatory- and immune- biology of neurodegeneration. These concepts may foster additional studies investigating the role of immunoproteasome as a potential target in neurodegenerative and neuro-immunological disorders.

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“…Proteasome inhibitors including bortezomib and carfilzomib have been used therapeutically for treatment of multiple myeloma and mantle cell lymphoma in patients (Kisselev et al, 2012; Teicher and Tomaszewski, 2015). In contrast, several drugs that increase 26S proteasome activity have potential applications in the treatment of neurodegenerative diseases (Myeku and Duff, 2018).…”

Section: Overview Of Human Proteasomementioning

confidence: 99%

Highlighting the Proteasome: Using Fluorescence to Visualize Proteasome Activity and Distribution

Jin

Leestemaker

Sapmaz

et al. 2019

Front. Mol. Biosci.

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Proteasomes are critical proteases in the cell responsible for the turnover of many cytoplasmic and nuclear proteins. They are essential for many cellular processes and various diseases are associated with their malfunctioning. Proteasome activity depends on the nature of the catalytic subunits, as well as the interaction with associated proteasome regulators. Here we describe various fluorescence-based methods to study proteasome function, highlighting the use of activity-based probes to study proteasome localization, dynamics, and activity in living cells.

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Targeting the 26S Proteasome To Protect Against Proteotoxic Diseases

Cited by 43 publications

References 102 publications

Eat it right: ER-phagy and recovER-phagy

Eat it right: ER-phagy and recovER-phagy

A Sentinel in the Crosstalk Between the Nervous and Immune System: The (Immuno)-Proteasome

Highlighting the Proteasome: Using Fluorescence to Visualize Proteasome Activity and Distribution

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