A “multi-omic” investigation of the effects of long wavelength ultraviolet light on primary human keratinocytes identifies NUPR1 as central stress response mediator

Long wavelength ultraviolet (UVA) light is the dominant oxidative stressor for the skin and promoting skin aging by yielding oxidation derived deleterious compounds. The dynamics of UVA/ROS induced reactive lipids and the responses to such stress in keratinocytes (KC), the major epidermal cell type, is only poorly understood. The aims of this study were to assess the photooxidation of phospholipids in KC, their contribution to transcriptional and translational responses, and to identify involved signaling pathways. We investigated the oxidized phospholipidome of cultured primary KC 0 h and 24 h post stress (UVA-1 or in vitro UV-oxidized phospholipids) with HPLC-MS/MS. We investigated the transcriptomic response 7 h after stress using microarrays and deep sequencing and changes in the proteome 24 h post stress using HPLC-MS. Lipidomics identified 173 UV-induced lipid species of which 89 declined to baseline levels after 24 h, and of which 141 were also induced by or contained in UVPAPC. We identified carbonylated, hydroxy and lysoPC species as regulated. The transcriptomic response showed a shared NRF2 signature for both stressors, and UPR/ER stress upon UVA. Upstream regulator analysis identified NUPR1 as novel high level stress response regulator, as knockdown of NUPR1 resulted in dysregulated expression of antioxidant, lipid detoxifying and cell cycle regulation genes.