The Amazing Ubiquitin-Proteasome System: Structural Components and Implication in Aging

Tsakiri, Eleni N.; Trougakos, Ioannis P.

doi:10.1016/bs.ircmb.2014.09.002

Cited by 63 publications

(96 citation statements)

References 452 publications

(505 reference statements)

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“…The ubiquitin-proteasome system (UPS) plays a major role in the degradation of misfolded and toxic proteins associated with aging and diseases [31, 32, 62, 63]. The UPS has also been implicated in cilia biology [64, 65].…”

Section: Resultsmentioning

confidence: 99%

Structural and Functional Recovery of Sensory Cilia in C. elegans IFT Mutants upon Aging

et al. 2016

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“…Furthermore, a variety of different enzymes, involved in substrate-polyubiquitination are affected by aging [144], thus influencing several essential cellular functions in favor of the progression of neurodegenerative diseases, accelerated senescence [145], reduced life span, carcinogenesis, genomic instability, increased susceptibility to (oxidative) stress, formation of protein aggregates [146] such as lipofuscin. As described before, lipofuscin is a highly oxidized material containing covalently cross-linked proteins, lipids and sugars that is very resistant to mammalian proteases and accumulates especially in post-mitotic cells over time, showing a strong negative correlation with the remaining life span [119], [147], [148], [149].…”

Section: Proteostasis In Agingmentioning

confidence: 99%

Happily (n)ever after: Aging in the context of oxidative stress, proteostasis loss and cellular senescence

et al. 2017

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Aging is a complex phenomenon and its impact is becoming more relevant due to the rising life expectancy and because aging itself is the basis for the development of age-related diseases such as cancer, neurodegenerative diseases and type 2 diabetes. Recent years of scientific research have brought up different theories that attempt to explain the aging process. So far, there is no single theory that fully explains all facets of aging. The damage accumulation theory is one of the most accepted theories due to the large body of evidence found over the years. Damage accumulation is thought to be driven, among others, by oxidative stress. This condition results in an excess attack of oxidants on biomolecules, which lead to damage accumulation over time and contribute to the functional involution of cells, tissues and organisms. If oxidative stress persists, cellular senescence is a likely outcome and an important hallmark of aging. Therefore, it becomes crucial to understand how senescent cells function and how they contribute to the aging process. This review will cover cellular senescence features related to the protein pool such as morphological and molecular hallmarks, how oxidative stress promotes protein modifications, how senescent cells cope with them by proteostasis mechanisms, including antioxidant enzymes and proteolytic systems. We will also highlight the nutritional status of senescent cells and aged organisms (including human clinical studies) by exploring trace elements and micronutrients and on their importance to develop strategies that might increase both, life and health span and postpone aging onset.

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“…A key component of the PN and a module for degradation of polypeptides is the ubiquitin‐proteasome pathway (UPP). Ubiquitin‐proteasome pathway is composed from the ubiquitin‐conjugating enzymes and the 26S proteasome; it is the site of protein synthesis quality control and is involved in the degradation of both normal short‐lived polypeptides and of misfolded or unfolded proteins . Polypeptide hydrolysis is catalysed by three peptidase sites located in the β1, β2 and β5 20S proteasome subunits, which bear caspase (C‐L)‐, trypsin (T‐L)‐ and chymotrypsin (CT‐L)‐like activities, respectively …”

Section: Introductionmentioning

confidence: 99%

“…Ubiquitin-proteasome pathway is composed from the ubiquitinconjugating enzymes and the 26S proteasome; it is the site of protein synthesis quality control and is involved in the degradation of both normal short-lived polypeptides and of misfolded or unfolded proteins. 4 Polypeptide hydrolysis is catalysed by three peptidase sites located in the β1, β2 and β5 20S proteasome subunits, which bear caspase (C-L)-, trypsin (T-L)-and chymotrypsin (CT-L)-like activities, respectively. 4,5 The imperative necessity of polypeptides to obtain their proper three-dimensional structure lies on the fact that they essentially are parts of complex protein machines, which are involved in virtually every cellular function, including genome stability and repair.…”

Section: Introductionmentioning

confidence: 99%

Non‐lethal proteasome inhibition activates pro‐tumorigenic pathways in multiple myeloma cells

Skorda

Sklirou

Sakellaropoulos

et al. 2019

J Cellular Molecular Medi

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Multiple myeloma (MM) is a haematological malignancy being characterized by clonal plasma cell proliferation in the bone marrow. Targeting the proteasome with specific inhibitors (PIs) has been proven a promising therapeutic strategy and PIs have been approved for the treatment of MM and mantle‐cell lymphoma; yet, while outcome has improved, most patients inevitably relapse. As relapse refers to MM cells that survive therapy, we sought to identify the molecular responses induced in MM cells after non‐lethal proteasome inhibition. By using bortezomib (BTZ), epoxomicin (EPOX; a carfilzomib‐like PI) and three PIs, namely Rub999, PR671A and Rub1024 that target each of the three proteasome peptidases, we found that only BTZ and EPOX are toxic in MM cells at low concentrations. Phosphoproteomic profiling after treatment of MM cells with non‐lethal (IC10) doses of the PIs revealed inhibitor‐ and cell type‐specific readouts, being marked by the activation of tumorigenic STAT3 and STAT6. Consistently, cytokine/chemokine profiling revealed the increased secretion of immunosuppressive pro‐tumorigenic cytokines (IL6 and IL8), along with the inhibition of potent T cell chemoattractant chemokines (CXCL10). These findings indicate that MM cells that survive treatment with therapeutic PIs shape a pro‐tumorigenic immunosuppressive cellular and secretory bone marrow microenvironment that enables malignancy to relapse.

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“…A hallmark of aging is the decreased ability to maintain protein function or protein homeostasis (proteostasis), which results in increased cellular damage and decline of cellular and organismal functions [26][27][28][29]. Compromised proteostasis in aged animals is in part due to reduced functionality of protein quality control mechanisms, thereby enhancing aggregation and accumulation of misfolded proteins [30][31][32][33][34]. Thus, protein complexes such as IFT particles that rely on defined stoichiometry of individual components [3,35,36] may be particularly vulnerable to aging.…”

Section: Introductionmentioning

confidence: 99%

Structural and Functional Recovery of Sensory Cilia in C. elegans IFT Mutants upon Aging

Maurya

Cornils

Tereshko

et al. 2017

Mechanisms of Development

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The majority of cilia are formed and maintained by the highly conserved process of intraflagellar transport (IFT). Mutations in IFT genes lead to ciliary structural defects and systemic disorders termed ciliopathies. Here we show that the severely truncated sensory cilia of hypomorphic IFT mutants in C. elegans transiently elongate during a discrete period of adult aging leading to markedly improved sensory behaviors. Age-dependent restoration of cilia morphology occurs in structurally diverse cilia types and requires IFT. We demonstrate that while DAF-16/FOXO is dispensable, the age-dependent suppression of cilia phenotypes in IFT mutants requires cell-autonomous functions of the HSF1 heat shock factor and the Hsp90 chaperone. Our results describe an unexpected role of early aging and protein quality control mechanisms in suppressing ciliary phenotypes of IFT mutants, and suggest possible strategies for targeting subsets of ciliopathies. Author SummaryCilia are 'antenna-like' structures that are present on nearly all cell types in animals. These structures are important for sensing and signaling external cues to the cell. Most cilia are formed by a protein transport process called 'intraflagellar transport' or IFT. Mutations in IFT genes result in severe cilia defects, and are causal to a large number of diverse human disorders called ciliopathies. Since the genes and processes by which cilia are formed are similar across species, studies in experimental models such as the nematode C. elegans can greatly inform our overall understanding of cilia formation and function. Here we report the surprising observation that the structures and functions of severely defective cilia in nematodes with disrupted IFT genes markedly improve upon aging. We find that protein quality control mechanisms that normally decline in aging are required for this age-dependent recovery of cilia structure. Our results raise the possibility that the effects of some mutations in IFT genes can be bypassed under specific conditions, thereby restoring cilia functions.

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The Amazing Ubiquitin-Proteasome System: Structural Components and Implication in Aging

Cited by 63 publications

References 452 publications

Structural and Functional Recovery of Sensory Cilia in C. elegans IFT Mutants upon Aging

Happily (n)ever after: Aging in the context of oxidative stress, proteostasis loss and cellular senescence

Non‐lethal proteasome inhibition activates pro‐tumorigenic pathways in multiple myeloma cells

Structural and Functional Recovery of Sensory Cilia in C. elegans IFT Mutants upon Aging

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