An inhibitor of ubiquitin conjugation and aggresome formation

An, Heeseon; Statsyuk, Alexander V.

doi:10.1039/c5sc01351h

Cited by 40 publications

(31 citation statements)

References 67 publications

(115 reference statements)

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“…Moreover, Neuro-2A cells treated with activity-based probe A3 (ABP A3), an E1 inhibitor of ubiquitin and Nedd8 pathways 25 , followed by cell lysis showed efficient inhibition of protein ubiquitination with a decrease of polyubiquitinated material (Fig. 2d ).…”

Section: Resultsmentioning

confidence: 99%

Dynamic recruitment of ubiquitin to mutant huntingtin inclusion bodies

Juenemann

Jansen

Riel

et al. 2018

Sci Rep

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Many neurodegenerative diseases, such as Huntington’s disease, are hallmarked by the formation of intracellular inclusion bodies (IBs) that are decorated with ubiquitin, proteasomes and chaperones. The apparent enrichment of ubiquitin and components involved in protein quality control at IBs suggests local ubiquitin-dependent enzymatic activity. In this study, we examine recruitment of ubiquitin to IBs of polyglutamine-expanded huntingtin fragments (mHtt) by using synthesized TAMRA-labeled ubiquitin moieties. We show that intracellular TAMRA-ubiquitin is dynamic at mHtt IBs and is incorporated into poly-ubiquitin chains of intracellular substrates, such as mHtt, in a conjugation-dependent manner. Furthermore, we report that mHtt IBs recruit catalytically active enzymes involved in (de)-ubiquitination processes based on novel activity-based probes. However, we also find that the overexpression of the GFP-ubiquitin reporter, unlike the endogenous ubiquitin and TAMRA-ubiquitin, becomes irreversibly sequestered as a ring-like structure around the mHtt IBs, suggesting a methodical disadvantage of GFP-tagged ubiquitin. Our data provide supportive evidence for dynamic recruitment of ubiquitin and ubiquitin (de)-conjugating activity at mHtt initiated IBs.

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Section: Resultsmentioning

confidence: 99%

Dynamic recruitment of ubiquitin to mutant huntingtin inclusion bodies

Juenemann

Jansen

Riel

et al. 2018

Sci Rep

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“…With aging, cellular proteostasis becomes less effective, hampering degradation of misfolded proteins, which in turn expose their hydrophobic domains and tend to form high-order complexes with other perinuclear/centrosomal-proximal proteins that are prone to aggregate into aggresomes (Kettern et al, 2011 ; Richter-Landsberg and Leyk, 2013 ; Seiberlich et al, 2013 ; Popovic et al, 2014 ; An and Statsyuk, 2015 ; Rodolfo et al, 2018 ). Then, upon lysosomal uptake of these aggregates via macroautophagy, highly cross-linked materials such as LF accumulate within the lysosomes (Höhn and Grune, 2013 ).…”

Section: Mechanisms Of Lipofuscin Accumulationmentioning

confidence: 99%

An Overview of the Role of Lipofuscin in Age-Related Neurodegeneration

et al. 2018

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Despite aging being by far the greatest risk factor for highly prevalent neurodegenerative disorders, the molecular underpinnings of age-related brain changes are still not well understood, particularly the transition from normal healthy brain aging to neuropathological aging. Aging is an extremely complex, multifactorial process involving the simultaneous interplay of several processes operating at many levels of the functional organization. The buildup of potentially toxic protein aggregates and their spreading through various brain regions has been identified as a major contributor to these pathologies. One of the most striking morphologic changes in neurons during normal aging is the accumulation of lipofuscin (LF) aggregates, as well as, neuromelanin pigments. LF is an autofluorescent lipopigment formed by lipids, metals and misfolded proteins, which is especially abundant in nerve cells, cardiac muscle cells and skin. Within the Central Nervous System (CNS), LF accumulates as aggregates, delineating a specific senescence pattern in both physiological and pathological states, altering neuronal cytoskeleton and cellular trafficking and metabolism, and being associated with neuronal loss, and glial proliferation and activation. Traditionally, the accumulation of LF in the CNS has been considered a secondary consequence of the aging process, being a mere bystander of the pathological buildup associated with different neurodegenerative disorders. Here, we discuss recent evidence suggesting the possibility that LF aggregates may have an active role in neurodegeneration. We argue that LF is a relevant effector of aging that represents a risk factor or driver for neurodegenerative disorders.

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“…The retrograde transport of misfolded proteins along the MT involves the negative-end-directed dynein and HDAC6 complex. Once the proteins reach the perinuclear site, aggresomes are formed around the MT-organizing center (MTOC) and are surrounded by a vimentin cage [29]. The overall structure of the aggresomes depends on the sequestered substrate and the cell.…”

Section: Mechanism Of Aggresome Formationmentioning

confidence: 99%

Virus-Induced Cytoplasmic Aggregates and Inclusions Are Critical Cellular Regulatory and Antiviral Factors

Olasunkanmi

Chen

Mageto

et al. 2020

Viruses

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RNA granules, aggresomes, and autophagy are key players in the immune response to viral infections. They provide countermeasures that regulate translation and proteostasis in order to rewire cell signaling, prevent viral interference, and maintain cellular homeostasis. The formation of cellular aggregates and inclusions is one of the strategies to minimize viral infections and virus-induced cell damage and to promote cellular survival. However, viruses have developed several strategies to interfere with these cellular processes in order to achieve productive replication within the host cells. A review on how these mechanisms could function as modulators of cell signaling and antiviral factors will be instrumental in refining the current scientific knowledge and proposing means whereby cellular granules and aggregates could be induced or prevented to enhance the antiviral immune response in mammalian cells.

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An inhibitor of ubiquitin conjugation and aggresome formation

Abstract: An inhibitor of ubiquitin activating E1 enzyme inhibits ubiquitin conjugation and aggresome formation.

Cited by 40 publications

References 67 publications

Dynamic recruitment of ubiquitin to mutant huntingtin inclusion bodies

Dynamic recruitment of ubiquitin to mutant huntingtin inclusion bodies

An Overview of the Role of Lipofuscin in Age-Related Neurodegeneration

Virus-Induced Cytoplasmic Aggregates and Inclusions Are Critical Cellular Regulatory and Antiviral Factors

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