Protein Degradation and the Pathologic Basis of Disease

Hanna, John; Guerra-Moreno, Ángel; Ang, Jessie; Micoogullari, Yagmur

doi:10.1016/j.ajpath.2018.09.004

Cited by 78 publications

(57 citation statements)

References 81 publications

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“…Intracellular pathways are affected by damaged proteins which then contribute to the etiology of different diseases. If protein degradation does not function properly due to altered proteolytic mechanisms, affected proteins accumulate in the cell, developing pathological conditions [87].…”

Section: Oxidative Stress and Mitochondrialmentioning

confidence: 99%

Inflammation and Oxidative Stress in Multiple Sclerosis: Consequences for Therapy Development

Pegoretti

Swanson

Bethea

et al. 2020

Oxidative Medicine and Cellular Longevity

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CNS inflammation is a major driver of MS pathology. Differential immune responses, including the adaptive and the innate immune system, are observed at various stages of MS and drive disease development and progression. Next to these immune-mediated mechanisms, other mediators contribute to MS pathology. These include immune-independent cell death of oligodendrocytes and neurons as well as oxidative stress-induced tissue damage. In particular, the complex influence of oxidative stress on inflammation and vice versa makes therapeutic interference complex. All approved MS therapeutics work by modulating the autoimmune response. However, despite substantial developments in the treatment of the relapsing-remitting form of MS, approved therapies for the progressive forms of MS as well as for MS-associated concomitants are limited and much needed. Here, we summarize the contribution of inflammation and oxidative stress to MS pathology and discuss consequences for MS therapy development.

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Section: Oxidative Stress and Mitochondrialmentioning

confidence: 99%

Inflammation and Oxidative Stress in Multiple Sclerosis: Consequences for Therapy Development

Pegoretti

Swanson

Bethea

et al. 2020

Oxidative Medicine and Cellular Longevity

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“…An important aspect of arsenic toxicity is its ability to covalently interact with free thiol groups in the amino acid sidechains of proteins . This may contribute to some of arsenic's proteotoxic effects . However, arsenic is also a potent oxidizing agent capable of generating oxygen‐free radicals and other oxidizing species .…”

Section: Resultsmentioning

confidence: 99%

Regulation of the unfolded protein response in yeast by oxidative stress

et al. 2019

Self Cite

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In the unfolded protein response (UPR), Ire1 activates Hac1 to coordinate the transcription of hundreds of genes to mitigate ER stress. Recent work in Caenorhabditis elegans suggests that oxidative stress inhibits this canonical Ire1 signalling pathway, activating instead an antioxidant stress response. We sought to determine whether this novel mode of UPR function also existed in yeast, where Ire1 has been best characterized. We show that the yeast UPR is also subject to inhibition by oxidative stress. Inhibition is mediated by a single evolutionarily conserved cysteine, and affects both luminal and membrane pathways of Ire1 activation. In yeast, Ire1 appears dispensable for resistance to oxidative stress and, therefore, the physiological significance of this pathway remains to be demonstrated.

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“…For each environmental perturbation, the proteome must be precisely and distinctly remodeled to ensure healthy and viable cells (1). Indeed, decreases in proteome integrity are hallmarks of many human diseases, including cancer, Alzheimer's disease, muscular dystrophies, and cystic fibrosis (2)(3)(4). Despite the importance of cellular stress response, our understanding of how cellular pathways interact during adaptation remains incomplete.…”

Section: Introductionmentioning

confidence: 99%

DIA-based systems biology approach unveils novel E3-dependent responses to a metabolic shift

Karayel

Michaelis

Mann

et al. 2020

Preprint

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Yeast Saccharomyces cerevisiae is a powerful model system for systems-wide biology screens and large-scale proteomics methods. Nearly complete proteomics coverage has been achieved owing to advances in mass spectrometry. However, it remains challenging to scale this technology for rapid and high-throughput analysis of the yeast proteome to investigate biological pathways on a global scale. Here we describe a systems biology workflow employing plate-based sample preparation and rapid, single-run data independent mass spectrometry analysis (DIA). Our approach is straightforward, easy to implement and enables quantitative profiling and comparisons of hundreds of nearly complete yeast proteomes in only a few days. We evaluate its capability by characterizing changes in the yeast proteome in response to environmental perturbations, identifying distinct responses to each of them, and providing a comprehensive resource of these responses. Apart from rapidly recapitulating previously observed responses, we characterized carbon source dependent regulation of the GID E3 ligase, an important regulator of cellular metabolism during the switch between gluconeogenic and glycolytic growth conditions. This unveiled new regulatory targets of the GID ligase during a metabolic switch. Our comprehensive yeast system read-out pinpointed effects of a single deletion or point mutation in the GID complex on the global proteome, allowing the identification and validation novel targets of the GID E3 ligase. Moreover, our approach allowed the identification of targets from multiple cellular pathways that display distinct patterns of regulation. Although developed in yeast, rapid whole proteome-based readouts can serve as comprehensive systems-level assay in all cellular systems.

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Protein Degradation and the Pathologic Basis of Disease

Cited by 78 publications

References 81 publications

Inflammation and Oxidative Stress in Multiple Sclerosis: Consequences for Therapy Development

Inflammation and Oxidative Stress in Multiple Sclerosis: Consequences for Therapy Development

Regulation of the unfolded protein response in yeast by oxidative stress

DIA-based systems biology approach unveils novel E3-dependent responses to a metabolic shift

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