A CULLINary ride across the secretory pathway: more than just secretion

Lu, Albert; Pfeffer, Suzanne R.

doi:10.1016/j.tcb.2014.02.001

Cited by 27 publications

(29 citation statements)

References 114 publications

(163 reference statements)

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“…Nonetheless, the protein content of exosomes derived from both groups of cells was associated with the Notch cellular pathway (Supporting Information Table 3). We also observed the presence of the protein ubiquitin in both exosome extracts, a molecule related to protein sorting to exosomes (Supporting Information Table 2) .…”

Section: Resultsmentioning

confidence: 80%

Hypoxia Inducible Factor-1α Potentiates Jagged 1-Mediated Angiogenesis by Mesenchymal Stem Cell-Derived Exosomes

et al. 2017

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Insufficient vessel growth associated with ischemia remains an unresolved issue in vascular medicine. Mesenchymal stem cells (MSCs) have been shown to promote angiogenesis via a mechanism that is potentiated by hypoxia. Overexpression of hypoxia inducible factor (HIF)-1α in MSCs improves their therapeutic potential by inducing angiogenesis in transplanted tissues. Here, we studied the contribution of exosomes released by HIF-1α-overexpressing donor MSCs (HIF-MSC) to angiogenesis by endothelial cells. Exosome secretion was enhanced in HIF-MSC. Omics analysis of miRNAs and proteins incorporated into exosomes pointed to the Notch pathway as a candidate mediator of exosome communication. Interestingly, we found that Jagged1 was the sole Notch ligand packaged into MSC exosomes and was more abundant in HIF-MSC than in MSC controls. The addition of Jagged1-containing exosomes from MSC and HIF-MSC cultures to endothelial cells triggered transcriptional changes in Notch target genes and induced angiogenesis in an in vitro model of capillary-like tube formation, and both processes were stimulated by HIF-1α. Finally, subcutaneous injection of Jagged 1-containing exosomes from MSC and HIF-MSC cultures in the Matrigel plug assay induced angiogenesis in vivo, which was more robust when they were derived from HIF-MSC cultures. All Jagged1-mediated effects could be blocked by prior incubation of exosomes with an anti-Jagged 1 antibody. All together, the results indicate that exosomes derived from MSCs stably overexpressing HIF-1α have an increased angiogenic capacity in part via an increase in the packaging of Jagged1, which could have potential applications for the treatment of ischemia-related disease. Stem Cells 2017;35:1747-1759.

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Section: Resultsmentioning

confidence: 80%

Hypoxia Inducible Factor-1α Potentiates Jagged 1-Mediated Angiogenesis by Mesenchymal Stem Cell-Derived Exosomes

et al. 2017

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“…One of the positive clones isolated by the screening was Cul7. Cul7 serves as the scaffold protein that brings together the adaptor protein Skp1, the substrate-targeting subunit Fbw8, and the really interesting (RING)-domain protein ROC1 to form a cullin RING E3 ubiquitin ligase complex2728.…”

Section: Resultsmentioning

confidence: 99%

“…To further address the potential physiological and pathological roles of Eag channels in the mammalian brain, herein we aim to ascertain the protein degradation mechanism of rat Eag1 (rEag1) proteins. We have identified cullin 7 (Cul7), a member of the cullin-based E3 ubiquitin ligase family2728, as a potential binding partner of rEag1. By employing biochemical, morphological, and electrophysiological methods to characterize this novel protein interaction between Cul7 and rEag1, we conclude that Cul7 plays an important role in the molecular machinery dictating the ubiquitin-dependent regulation of rEag1 K + channels in both the ER and the plasma membrane.…”

mentioning

confidence: 99%

Cullin 7 mediates proteasomal and lysosomal degradations of rat Eag1 potassium channels

Hsu

Yu²,

Fang

et al. 2017

Sci Rep

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Mammalian Eag1 (Kv10.1) potassium (K+) channels are widely expressed in the brain. Several mutations in the gene encoding human Eag1 K+ channel have been associated with congenital neurodevelopmental anomalies. Currently very little is known about the molecules mediating protein synthesis and degradation of Eag1 channels. Herein we aim to ascertain the protein degradation mechanism of rat Eag1 (rEag1). We identified cullin 7 (Cul7), a member of the cullin-based E3 ubiquitin ligase family, as a novel rEag1 binding partner. Immunoprecipitation analyses confirmed the interaction between Cul7 and rEag1 in heterologous cells and neuronal tissues. Cul7 and rEag1 also exhibited significant co-localization at synaptic regions in neurons. Over-expression of Cul7 led to reduced protein level, enhanced ubiquitination, accelerated protein turn-over, and decreased current density of rEag1 channels. We provided further biochemical and morphological evidence suggesting that Cul7 targeted endoplasmic reticulum (ER)- and plasma membrane-localized rEag1 to the proteasome and the lysosome, respectively, for protein degradation. Cul7 also contributed to protein degradation of a disease-associated rEag1 mutant. Together, these results indicate that Cul7 mediates both proteasomal and lysosomal degradations of rEag1. Our findings provide a novel insight to the mechanisms underlying ER and peripheral protein quality controls of Eag1 channels.

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“…TNF-α is then secreted into the extracellular space or remains inside the cells in the form of secretary vesicles. Studies of other intracellular vesicles have shown that the destination of these vesicles is regulated by ubiquitination at their cytoplasmic surface [35] . It is conceivable that the miR-124-mediated decrease of USP2 and USP14 resulted in increased ubiquitination of vesicle protein(s), which perhaps led to fusion of the vesicles with lysosomes and degradation of TNF-α.…”

Section: Discussionmentioning

confidence: 99%

MicroRNA-124 negatively regulates LPS-induced TNF-α production in mouse macrophages by decreasing protein stability

Sun

Qin

et al. 2016

Acta Pharmacol Sin

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Aim: MicroRNAs play pivotal roles in regulation of both innate and adaptive immune responses. In the present study, we investigated the effects of microRNA-124 (miR-124) on production of the pro-inflammatory cytokine TNF-α in lipopolysaccharide (LPS)-treated mouse macrophages. Methods: Mouse macrophage cell line RAW264.7 was stimulated with LPS (100 ng/mL). The levels of miR-124 and TNF-α mRNA were evaluated using q-PCR. ELISA and Western blotting were used to detect TNF-α protein level in cell supernatants and cells, respectively. 3′-UTR luciferase reporter assays were used to analyze the targets of miR-124. For in vivo experiments, mice were injected with LPS (30 mg/kg, ip). Results: LPS stimulation significantly increased the mRNA level of miR-124 in RAW264.7 macrophages in vitro and mice in vivo. In RAW264.7 macrophages, knockdown of miR-124 with miR-124 inhibitor dose-dependently increased LPS-stimulated production of TNF-α protein and prolonged the half-life of TNF-α protein, but did not change TNF-α mRNA levels, whereas overexpression of miR-124 with miR-124 mimic produced the opposite effects. Furthermore, miR-124 was found to directly target two components of deubiquitinating enzymes: ubiquitin-specific proteases (USP) 2 and 14. Knockdown of USP2 or USP14 accelerated protein degradation of TNF-α, and abolished the effect of miR-124 on TNF-α protein stability. Conclusion: miR-124, targeting USP2 and USP14, negatively regulates LPS-induced TNF-α production in mouse macrophages, suggesting miR-124 as a new therapeutic target in inflammation-related diseases.

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A CULLINary ride across the secretory pathway: more than just secretion

Cited by 27 publications

References 114 publications

Hypoxia Inducible Factor-1α Potentiates Jagged 1-Mediated Angiogenesis by Mesenchymal Stem Cell-Derived Exosomes

Hypoxia Inducible Factor-1α Potentiates Jagged 1-Mediated Angiogenesis by Mesenchymal Stem Cell-Derived Exosomes

Cullin 7 mediates proteasomal and lysosomal degradations of rat Eag1 potassium channels

MicroRNA-124 negatively regulates LPS-induced TNF-α production in mouse macrophages by decreasing protein stability

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