A novel role for NUPR1 in the keratinocyte stress response to UV oxidized phospholipids

Marie-Sophie Narzt,Ionela-Mariana Nagelreiter,Olga Oskolkova,Valery N Bochkov,Julie Latreille,Maria Fedorova,Zhixu Ni,Fernando J Sialana,Gert Lubec,Manuel Filzwieser,Maria Laggner,Martin Bilban,Michael Mildner,Erwin Tschachler,Johannes Grillari,Florian Gruber

doi:10.1016/j.redox.2018.11.006

Abstract

Ultraviolet light is the dominant environmental oxidative skin stressor and a major skin aging factor. We studied which oxidized phospholipid (OxPL) mediators would be generated in primary human keratinocytes (KC) upon exposure to ultraviolet A light (UVA) and investigated the contribution of OxPL to UVA responses. Mass spectrometric analysis immediately or 24 h post UV stress revealed significant changes in abundance of 173 and 84 lipid species, respectively. We identified known and novel lipid species including known bioactive and also potentially reactive carbonyl containing species. We found indication for selective metabolism and degradation of selected reactive lipids. Exposure to both UVA and to in vitro UVA - oxidized phospholipids activated, on transcriptome and proteome level, NRF2/antioxidant response signaling, lipid metabolizing enzyme expression and unfolded protein response (UPR) signaling. We identified NUPR1 as an upstream regulator of UVA/OxPL transcriptional stress responses and found this protein to be expressed in the epidermis. Silencing of NUPR1 resulted in augmented expression of antioxidant and lipid detoxification genes and disturbed the cell cycle, making it a potential key factor in skin reactive oxygen species (ROS) responses intimately involved in aging and pathology.

Highlights

The human skin is the organ most exposed to environmental oxidative assaults that cause cell damage, promote aging and result in pathologies
Throughout this study we compared the effects of ultraviolet A light (UVA) exposure on keratinocyte lipidome, transcriptome and proteome to the effects of externally addend UVA-oxidized phospholipids
We hypothesized that similar to what we observed in FB in keratinocytes UVAoxidized phospholipids would account for a part of the transcriptional UVA response

Summary

Introduction

The human skin is the organ most exposed to environmental oxidative assaults that cause cell damage, promote aging and result in pathologies. The dominant extrinsic oxidizing factor is ultraviolet A light (UVA, 340–400 nm) which can penetrate deeply into the skin and modifies nucleic acids, proteins and lipids [74]. The UVA induced DNA damage is mutagenic and promotes photoaging [4], the premature aging phenotype of excessively sun exposed skin [67]. Reactive oxidized lipid species modify DNA and proteins such as histones [20] thereby affecting cell signaling and epigenetics [26]. Bi-reactive lipid oxidation products like bis-aldehydes crosslink macromolecules [65] which can be detected in photo-aged skin [46,79]. To the chemically reactive lipids, potent lipid signaling molecules are formed by UV through enzymes [43] or non-enzymatically

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Results

Conclusion