Impairment of the Ubiquitin-Proteasome Pathway in RPE Alters the Expression of Inflammation Related Genes

Liu, Zhenzhen; Qin, Tingyu; Zhou, Jilin; Taylor, Allen; Sparrow, Janet R.; Shang, Fu

doi:10.1007/978-1-4614-3209-8_31

Cited by 22 publications

(22 citation statements)

References 65 publications

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“…A previous study found that deficiency in ubiquitin ligase led to the accumulation of neurofilament light chain and to neurodegeneration 26 . Impairment of the ubiquitin-proteasome pathway can also disrupt signal transduction pathways resulting in inflammation and angiogenesis; both are important features of AMD 27 . Therefore, dysfunction of ubiquitin protein ligase (E3) may lead to the accumulation of extracellular deposits (a component of drusen), degeneration of photoreceptors and the retinal pigment epithelium (RPE), and late-stage AMD.…”

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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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%

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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“…It has been shown that multiple risk factors for AMD are associated with changes in the physiological functions of RPE cells; for example, oxidants can induce apoptosis of RPE cells [ 13 ] and abnormal secretion of inflammatory factors [ 14 ]. Cigarette smoke extract can also induce apoptosis of RPE cells [ 15 ] and up-regulation of vascular endothelial growth factor (VEGF) expression [ 16 ], while a high-fat diet may result in up-regulation of interleukin-8 (IL-8) and VEGF expressions in RPE cells [ 17 ].…”

Section: Introductionmentioning

confidence: 99%

Cyclic stretch induced-retinal pigment epithelial cell apoptosis and cytokine changes

Wang

et al. 2017

BMC Ophthalmol

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BackgroundThe pathogenesis of age-related macular degeneration (AMD) is complex. It has been shown that vitreomacular traction (VMT) plays a role in the pathogenesis of AMD. We speculate that the continuous stretch induced by VMT might impair the function of retinal pigment epithelium (RPE) cells and it might also be involved in the progression of AMD.MethodsCultured ARPE-19 cells were subjected to cyclic stretch on the Flexcell Strain system at a level of 25% increment on the surface area for 8 h, 14 h, 20 h, 24 h. In another group, the stretch was withdrawn at 14 h and the cell cultured for another 6 h. Then, we observed the changes in morphology, apoptosis and expression of interleukin 6 (IL6) and vascular endothelial growth factor (VEGF) in RPE cells under stretch.ResultsWe found that stretch induced the RPE cells to change from a spreading shape into a rounded shape, and that the morphological changes were positively correlated with the duration of the stretch. The expression of pFAK397 and pRac1/cdc42 were elevated in a time-dependent fashion. The stretch resulted in an increase in the apoptosis ratio, with Bcl2, Bax and p53 also showing time-dependent changes. In addition, up-regulation of IL6 and VEGF expression levels was also observed. After withdrawal of the stretch, all of these changes were significantly diminished.ConclusionStretch may induce morphological, cell apoptosis, and up-regulation of cytokines changes in RPE cells, indicating that cyclic stretching may participate in the progression of AMD by impeding the functions of the RPE.

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“…However, the exact function of CagA in the activation of NF-κB and the NF-κB-dependent inflammatory response have not been well characterized. Emerging evidence indicated that post-translational modification, including ubiquitination and acetylation, has important roles in various biological events, including inflammation (55)(56)(57)(58)(59)(60). Among these, the acetylation of the NF-κB p65 sub-unit has been shown to have an important role in its activation (27)(28)(29).…”

Section: Discussionmentioning

confidence: 99%

Helicobacter pylori cytotoxin-associated gene A activates tumor necrosis factor-α and interleukin-6 in gastric epithelial cells through P300/CBP-associated factor-mediated nuclear factor-κB p65 acetylation

Lin

Chen

et al. 2015

Molecular Medicine Reports

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Helicobacter pylori‑initiated chronic gastritis is characterized by the cytotoxin‑associated gene (Cag) pathogenicity island‑dependent upregulation of pro‑inflammatory cytokines in gastric epithelial cells, which is largely mediated by the activation of nuclear factor (NF)‑κB as a transcription factor. However, the precise regulation of NF‑κB activation, particularly post‑translational modifications in the CagA‑induced inflammatory response, has remained elusive. The present study showed that Helicobacter pylori CagA, an important virulence factor, induced the expression of P300/CBP‑associated factor (PCAF) in gastric epithelial cells. Further study revealed that PCAF was able to physically associate with the NF‑κB p65 sub‑unit and enhance its acetylation. More importantly, PCAF‑induced p65 acetylation was shown to contribute to p65 phosphorylation and further upregulation of tumor necrosis factor (TNF)‑α and interleukin (IL)‑6 in gastric adenocarcinoma cells. In conclusion, the results of the present study indicated that Helicobacter pylori CagA enhanced TNF‑α and IL‑6 in gastric adenocarcinoma cells through PCAF‑mediated NF‑κB p65 sub‑unit acetylation.

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Impairment of the Ubiquitin-Proteasome Pathway in RPE Alters the Expression of Inflammation Related Genes

Cited by 22 publications

References 65 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

Cyclic stretch induced-retinal pigment epithelial cell apoptosis and cytokine changes

Helicobacter pylori cytotoxin-associated gene A activates tumor necrosis factor-α and interleukin-6 in gastric epithelial cells through P300/CBP-associated factor-mediated nuclear factor-κB p65 acetylation

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