The ubiquitin system

Nath, Deepa; Shadan, Sadaf

doi:10.1038/458421a

Cited by 53 publications

(54 citation statements)

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“…Moreover, ablation of the UBE3D protein leads to retinal structural changes and abnormal ERG in UBE3D þ / À heterozygous mice. Therefore, this study demonstrates a potential link between AMD and the UPS 17 .…”

Section: Discussionmentioning

confidence: 99%

“…The cellular ubiquitin-proteasome system, which is important for regulating the intracellular sorting and degradation of proteins, plays a central role in cellular protein homeostasis 17,18 . The ubiquitin-conjugating system requires three enzymes: E1, an ubiquitin-activating enzyme; E2, a ubiquitin-conjugating enzyme; and E3, a ubiquitin ligase [19][20][21] .…”

Section: Discussionmentioning

confidence: 99%

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Whole-exome sequencing implicates UBE3D in age-related macular degeneration in East Asian populations

Huang

Xie

et al. 2015

Nat Commun

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Age-related macular degeneration (AMD) is a leading cause of irreversible central blindness among the elderly worldwide. We use exome sequencing to analyse nonsynonymous singlenucleotide variants (SNVs) across the whole genome of 216 neovascular AMD cases and 1,553 controls. As a follow-up validation, we evaluate 3,772 neovascular AMD cases and 6,942 controls from five independent cohorts in the East Asian population. Here we show strong evidence of an association at a novel, missense SNV, rs7739323, which is located in the ubiquitin protein ligase E3D (UBE3D) gene (P meta ¼ 1.46 Â 10 À 9 , odds ratio (OR) ¼ 0.74, 95% confidence interval (CI): 0.63-0.88). Furthermore, ablation of the UBE3D protein lead to an abnormal amount of pigment granules deposited in retinal pigment epithelium microvilli area and an abnormal response on electroretinography (ERG) in UBE3D þ / À heterozygous mice. Our findings indicate that the ubiquitin-proteasome system may play a role in the pathogenesis of neovascular AMD.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Whole-exome sequencing implicates UBE3D in age-related macular degeneration in East Asian populations

Huang

Xie

et al. 2015

Nat Commun

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“…As a whole, the UPS is responsible for the degradation of up to 80% of short-lived proteins in any cell of the body (60). The targeting of proteins for degradation depends on the action of a complex enzymatic system that activates ubiquitin molecules to be bonded to certain lysine residues in the target protein (61).…”

Section: European Journal Of Endocrinologymentioning

confidence: 99%

MECHANISMS IN ENDOCRINOLOGY: Hypothalamic inflammation and nutrition

Araujo

Moraes

Cintra

et al. 2016

European Journal of Endocrinology

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Selected subpopulations of hypothalamic neurons play important roles in the regulation of whole body energy homeostasis. Studies have shown that the saturated fats present in large amounts in western diets can activate an inflammatory response in the hypothalamus, affecting the capacity of such neurons to respond appropriately to satiety and adipostatic signals. In the first part of this review, we will explore the mechanisms behind saturated fatty acid-induced hypothalamic dysfunction. Next, we will present and discuss recent studies that have identified the mechanisms that mediate some of the anti-inflammatory actions of unsaturated fatty acids in the hypothalamus and the potential for exploring these mechanisms to prevent or treat obesity.

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“…The nature of the specific lysine polymer involved in the linkage affects the activity of the target protein in different ways. For example, K48-Polyub tags the target protein to be degraded by the proteasome, and K29-Polyub is considered as an indicator of subsequent lysosomal degradation (1). During the last few years K63-Polyub has emerged as a novel posttranslational modification of remarkable functional interest for fine-tuning signal transduction pathways (4).…”

mentioning

confidence: 99%

“…Subsequently, the E3 ligase polymerizes additional ubiquitin molecules to form an extending polymer involving lysine side chains and the C-terminus glycine from the incoming ubiquitin monomer. E3 ligases provide substrate specificity to the pathway and are classified into two groups according to the presence of catalytic domains HECT or RING (1).…”

mentioning

confidence: 99%

Lysine 63 Polyubiquitination in Immunotherapy and in Cancer-promoting Inflammation

Martínez-Forero

Rouzaut²,

Palazón³

et al. 2009

Clinical Cancer Research

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Covalent and reversible post-translational modifications of proteins are a common theme in signaling. Ubiquitin conjugation was originally described to target proteins to proteasomal degradation by ubiquitin polymerization involving lysine (K) 48 residues. Differently linked polymers of polyubiquitin have been found that modify proteins without targeting to proteasomal degradation. Instead this pathway creates docking sites for signaling scaffolds that are key to control the nuclear factor-κB (NF-κB) pathway. Indeed TRAF-2, TRAF-6, and TRAF-3 are E3 ubiquitin ligases that form K63-linked ubiquitin polymers. Therefore signaling via TNF family receptors, IL1R, IL-18R, T-cell receptor (TCR), and Toll-like receptors (TLR) use this type of post-translational modification. Specific enzymes exist (DUBs) that deactivate this system, degrading K63 polyubiquitin chains. Interestingly, mice deficient in these deubiquitinases develop autoimmunity and inflammation. In carcinogenesis, the K63 polyubiquitin pathway is possibly critical for inflammation-driven tumor promotion. The pathway is also critically involved in costimulation of tumor immunity/immunotherapy as well as in the biology of malignant cells themselves. The elements of this new signaling paradigm offer the opportunity for therapeutic exploitation and drug discovery. Cellular protein function is often regulated through posttranslational covalent modifications that share common characteristics. First, they are reversible. Specific enzymes are responsible for attaching chemical groups (phosphate, acetyl), and other enzymes have the mission of removing them. Second, the modification takes place on specific amino acid residues of the target protein (serine, tyrosine, threonine, lysine). Third, post-translational modifications change the activities of the target protein.Ubiquitin is a 76-amino acid protein abundantly present in all eukaryotic cells. Post-translational attachment of ubiquitin to target proteins is a well-known control mechanism in diverse and essential cellular activities ranging from apoptosis to intracellular protein trafficking. Ubiquitin can be linked to proteins using accessible lysine, cysteine, or the N-terminal amino acid. The general scheme of the ubiquitin conjugation pathway is as follows (Fig. 1A): (1) An enzyme, E1 binds to ubiquitin and activates it for reaction in an ATP-dependent fashion; (2) E2 or ubiquitin conjugase carries ubiquitin to an ubiquitin ligase E3 protein that binds to the target protein; (3) E3 ligases couple an ubiquitin moiety to the amino terminus of the substrate protein. Subsequently, the E3 ligase polymerizes additional ubiquitin molecules to form an extending polymer involving lysine side chains and the C-terminus glycine from the incoming ubiquitin monomer. E3 ligases provide substrate specificity to the pathway and are classified into two groups according to the presence of catalytic domains HECT or RING (1).As mentioned, once a monomer of ubiquitin is attached, it can be extended to form polymers throu...

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The ubiquitin system

Cited by 53 publications

References 0 publications

Whole-exome sequencing implicates UBE3D in age-related macular degeneration in East Asian populations

Whole-exome sequencing implicates UBE3D in age-related macular degeneration in East Asian populations

MECHANISMS IN ENDOCRINOLOGY: Hypothalamic inflammation and nutrition

Lysine 63 Polyubiquitination in Immunotherapy and in Cancer-promoting Inflammation

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