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Nrf3 promotes UV-induced keratinocyte apoptosis through suppression of cell adhesion


Siegenthaler, Beat; Defila, Claudia; Muzumdar, Sukalp; Beer, Hans-Dietmar; Meyer, Michael; Tanner, Sandra; Bloch, Wilhelm; Blank, Volker; Schäfer, Matthias; Werner, Sabine (2018). Nrf3 promotes UV-induced keratinocyte apoptosis through suppression of cell adhesion. Cell Death and Differentiation, 25(10):1749-1765.

Abstract

The transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) is a key regulator of the cellular stress response, but the biological functions of the related Nrf3 protein are largely unknown. Here we demonstrate a novel pro-apoptotic function of Nrf3 in mouse and human keratinocytes. In response to UV irradiation, Nrf3-deficient keratinocytes were protected from apoptosis in vitro and in vivo. The protective function was also seen under oxidative or hyperosmotic stress conditions, but not when apoptosis was induced by disruption of cell-matrix interactions. Mechanistically, we show that Nrf3-deficient keratinocytes exhibit stronger cell-cell and cell-matrix adhesion, which correlates with higher cell surface integrin levels and enhanced activation of focal adhesion kinase. Nrf3-deficient cells also formed more and larger focal adhesions and exhibited a higher motility. These results suggest that the strong expression of Nrf3 in basal keratinocytes promotes their elimination in response to DNA damage-inducing agents, thereby preventing accumulation of mutated stem and transit amplifying cells in the epidermis.

Abstract

The transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) is a key regulator of the cellular stress response, but the biological functions of the related Nrf3 protein are largely unknown. Here we demonstrate a novel pro-apoptotic function of Nrf3 in mouse and human keratinocytes. In response to UV irradiation, Nrf3-deficient keratinocytes were protected from apoptosis in vitro and in vivo. The protective function was also seen under oxidative or hyperosmotic stress conditions, but not when apoptosis was induced by disruption of cell-matrix interactions. Mechanistically, we show that Nrf3-deficient keratinocytes exhibit stronger cell-cell and cell-matrix adhesion, which correlates with higher cell surface integrin levels and enhanced activation of focal adhesion kinase. Nrf3-deficient cells also formed more and larger focal adhesions and exhibited a higher motility. These results suggest that the strong expression of Nrf3 in basal keratinocytes promotes their elimination in response to DNA damage-inducing agents, thereby preventing accumulation of mutated stem and transit amplifying cells in the epidermis.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Dermatology Clinic
Dewey Decimal Classification:610 Medicine & health
Language:English
Date:1 November 2018
Deposited On:24 Aug 2018 17:37
Last Modified:01 Nov 2018 01:12
Publisher:Nature Publishing Group
ISSN:1350-9047
OA Status:Green
Free access at:PubMed ID. An embargo period may apply.
Publisher DOI:https://doi.org/10.1038/s41418-018-0074-y
PubMed ID:29487353

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