Back to Search
Start Over
Ultraviolet B irradiation induced Nrf2 degradation occurs via activation of TRPV1 channels in human dermal fibroblasts.
- Source :
-
Free radical biology & medicine [Free Radic Biol Med] 2019 Sep; Vol. 141, pp. 220-232. Date of Electronic Publication: 2019 Jun 18. - Publication Year :
- 2019
-
Abstract
- Ultraviolet (UV) irradiation causes cellular oxidative stress. Under redox imbalance, Keap1-dependent Nrf2 degradation is minimal. In this study, we examined the role of Ca <superscript>2+</superscript> in Nrf2 homeostasis after UVB irradiation using human dermal fibroblasts. UVB irradiation stimulates 12-lipoxygenase and the product 12-hydroxyeicosatetraenoic acid then activates TRPV1 increasing the cell's cytosolic Ca <superscript>2+</superscript> concentration. UVB irradiation induced reactive oxygen species generation and apoptosis are inhibited in the absence of Ca <superscript>2+</superscript> or in the presence of either a 12-lipoxygenase inhibitor or a TRPV1 inhibitor during and after UVB irradiation. Thus, the Ca <superscript>2+</superscript> increase via TRPV1 is a critical factor in UVB irradiation induced oxidative stress. UVB irradiation induces a Ca <superscript>2+</superscript> dependent Nrf2 degradation and thus activation of TRPV1 with 12-hydroxyeicosatetraenoic acid also decreasing Nrf2 levels. UVB irradiation induced Nrf2 degradation is inhibited by co-treatment of cells with W-7, cyclosporin A, SB-216763 or MG-132, which are inhibitors of calmodulin, calcineurin, GSK3β and the proteasome, respectively. Furthermore, UVB irradiation in parallel induces GSK3β dephosphorylation in a Ca <superscript>2+</superscript> dependent manner. Co-immunoprecipitation showed that UVB irradiation induces an increase in Nrf2 phosphorylation, an increase in the binding of β-TrCP and Nrf2, and an increase in Nrf2 ubiquitination; these effects are all Ca <superscript>2+</superscript> dependent. These findings suggest that UVB irradiation induced GSK3β activation in a Ca <superscript>2+</superscript> dependent manner, which then stimulates the phosphorylation and ubiquitination of Nrf2 via β-TrCP. Indeed, silencing of β-TrCP was found to inhibit UVB irradiation-induced oxidative stress, Nrf2 degradation and apoptosis, while it had no effect on the Ca <superscript>2+</superscript> increase. Taken together, our results suggest that a Ca <superscript>2+</superscript> influx via TRPV1 is responsible for UVB irradiation-induced Nrf2 degradation and that modulation of the Ca <superscript>2+</superscript> -calmodulin-calcineurin-GSK3β-Nrf2-β-TrCP-Cullin-1 pathway may explain Ca <superscript>2+</superscript> dependent Nrf2 degradation.<br /> (Copyright © 2019 Elsevier Inc. All rights reserved.)
- Subjects :
- Antioxidants metabolism
Apoptosis
Calcium metabolism
Cell Proliferation
Fibroblasts radiation effects
Free Radicals metabolism
Glycogen Synthase Kinase 3 beta metabolism
Humans
Phosphorylation
Proteasome Endopeptidase Complex metabolism
Reactive Oxygen Species metabolism
Skin metabolism
Calcineurin metabolism
Fibroblasts metabolism
NF-E2-Related Factor 2 metabolism
Skin radiation effects
TRPV Cation Channels metabolism
Ultraviolet Rays
Subjects
Details
- Language :
- English
- ISSN :
- 1873-4596
- Volume :
- 141
- Database :
- MEDLINE
- Journal :
- Free radical biology & medicine
- Publication Type :
- Academic Journal
- Accession number :
- 31220549
- Full Text :
- https://doi.org/10.1016/j.freeradbiomed.2019.06.020