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

Ultraviolet light is the dominant environmental oxidative skin stressor and a major factor in skin aging. We studied which oxidized phospholipid (OxPL) species 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 revealed dynamic UV-induced changes in abundance of 174 lipid species within 24 hours. We identified known and novel bioactive and also chemically reactive lipids and found indication for selective degradation of selected reactive lipid classes. 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 signaling. We further identified NUPR1 as an upstream regulator of UVA/OxPL transcriptional responses and found this protein expressed in the epidermis and permissive to modification by oxidized lipids. 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.