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

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.

Epigenetic treatment of dermatologic disorders

“…Representing the outermost surface of the body, skin is uniquely vulnerable to a plethora of environmental insults. Exposure to harmful chemicals, xenobiotics, oxidative stress, and solar UV‐radiation is mitigated by various protective mechanisms that rely on signaling networks and the expression of proteins involved in the detoxification of compounds or reactive oxygen species (Dinkova‐Kostova et al, ; Dodson et al, ; Hiebert et al, ; Jadkauskaite et al, ; Raghunath et al, ; Siegenthaler et al, ; Sivandzade, Prasad, Bhalerao, & Cucullo, ; Tonelli, Chio, & Tuveson, ; Vega, Krajisnik, Zhang, & Wondrak, ; Yamamoto, Kensler, & Motohashi, ).…”

“…A relative of Nrf2, Nrf3, is a negative regulator of antioxidant response (Chatterjee et al, ; Raghunath et al, ) and is more strongly expressed in basal keratinocytes (Siegenthaler et al, ). This heightened expression helps to eliminate the buildup of tumorigenic cells in the epidermis in response to DNA damage‐inducing agents (Siegenthaler et al, ). The opposing, complementary functions of Nrf2 and Nrf3 further underscore a critical dilemma faced in arbitrarily overactivating Nrf2 (Dodson et al, ; Ikehata & Yamamoto, ; Menegon et al, ; Rabbani, Xue, et al, ; Silva‐Palacios et al, ; Sova & Saso, ).…”

“…Although mitochondrial dysfunction adversely affects primarily nonregenerative tissue, the neuro- More than 250 genes (of approximately 20,000 protein-coding genes in the human genome (Salzberg, 2018)) are impacted by changes in the expression of the transcription factor nuclear factor erythroid 2 (NFE2)-related factor 2 (Nrf2) (Dodson et al, 2019). Nrf2, a member of the Cap'n'Collar basic-region leucine zipper (CNC-bZIP) transcription factor family (Chatterjee et al, 2018;Chevillard & Blank, 2011;Dodson et al, 2019;Loboda, Damulewicz, Pyza, Jozkowicz, & Dulak, 2016;Raghunath et al, 2018;Siegenthaler et al, 2018;Sivandzade et al, 2019;Tonelli et al, 2018;Yamamoto et al, 2018), binds the nuclear antioxidant response element (ARE) in crosstalk with many other signaling cascades that coordinate a multitude of cellular processes, including redox balance and protective antioxidant phases I-III drug/xenobiotic detoxification responses, protein homeostasis, DNA repair, carbohydrate and lipid metabolism, iron homeostasis, transcriptional regulation, and mitochondrial function (Dodson et al, 2019).…”

“…For instance, induced Nrf2 activation is believed to be favorable in helping to prevent or delay the onset of neurodegenerative diseases and cancer (Al-Sawaf et al, 2015;Buendia et al, 2016;Dinkova-Kostova et al, 2018;Dodson et al, 2019;Loboda et al, 2016;Lu et al, 2016;Silva-Palacios et al, 2018;Sivandzade et al, 2019;Sova & Saso, 2018), while overactivation can progress tumorigenesis and accelerate metastasis (Badrinath & Yoo, 2018;Dodson et al, 2019;Menegon, Columbano, & Giordano, 2016;Rabbani, Xue, Weickert, & Thornalley, 2018;Sabharwal & Schumacker, 2014;Silva-Palacios et al, 2018;Sova & Saso, 2018). Interestingly, although many studies link decreased activity of Nrf2 in the elderly (as part of the aging process, particularly in the brain) to an increased prevalence of (neuro)degenerative diseases (Silva-Palacios et al, 2018;Sivandzade et al, 2019), the decreased activity may actually be serving a protective role against UV-induced carcinogenesis in skin (Siegenthaler et al, 2018).…”

“…Like Nrf2, Nrf3 (nuclear factor erythroid 2-related factor 3) is a CNC-bZIP transcription factor (Chevillard & Blank, 2011;Dodson et al, 2019;Raghunath et al, 2018;Siegenthaler et al, 2018;Yamamoto et al, 2018). However, whereas Nrf2 is a pro-survival, prolongevity protein (Silva-Palacios et al, 2018), the biological function of Nrf3 is pro-apoptotic (Siegenthaler et al, 2018). A relative of Nrf2, Nrf3, is a negative regulator of antioxidant response (Chatterjee et al, 2018;Raghunath et al, 2018) and is more strongly expressed in basal keratinocytes (Siegenthaler et al, 2018).…”