Autophagy Is Induced by UVA and Promotes Removal of Oxidized Phospholipids and Protein Aggregates in Epidermal Keratinocytes

Abstract

The skin is exposed to environmental insults such as UV light that cause oxidative damage to macromolecules. A centerpiece in the defense against oxidative stress is the Nrf2 (nuclear factor (erythroid-derived-2)-like 2)-mediated transcriptional upregulation of antioxidant and detoxifying enzymes and the removal of oxidatively damaged material. Autophagy has an important role in the intracellular degradation of damaged proteins and entire organelles, but its role in the epidermis has remained elusive. Here, we show that both UVA and UVA-oxidized phospholipids induced autophagy in epidermal keratinocytes. Oxidative stressors induced massive accumulation of high-molecular-weight protein aggregates containing the autophagy adaptor protein p62/SQSTM1 in autophagy-deficient (autophagy-related 7 (ATG7) negative) keratinocytes. Strikingly, even in the absence of exogenous stress, the expression of Nrf2-dependent genes was elevated in autophagy-deficient keratinocytes. Furthermore, we show that autophagy-deficient cells contained significantly elevated levels of reactive oxidized phospholipids. Thus, our data demonstrate that autophagy is crucial for both the degradation of proteins and lipids modified by environmental UV stress and for limiting Nrf2 activity in keratinocytes. Lipids that promote inflammation and tissue damage because of their reactivity and signaling functions are commonly observed in aged and diseased skin, and thus targeting autophagy may be a promising strategy to counteract the damage promoted by excessive lipid oxidation.

Nrf2 deficiency causes lipid oxidation, inflammation, and matrix-protease expression in DHA-supplemented and UVA-irradiated skin fibroblasts

“…Oxidized PAPC comprises electrophilic lipids that structurally resemble 15d Prostaglandin J2 which can form adducts with KEAP1 and thereby activate Nrf2 [72]. However, we have also recently described that in KC high concentrations of oxidized phospholipids may inhibit autophagy, thereby causing accumulation of SQSTM1/p62 protein which competes with NRF2 for KEAP1 binding, a recently discovered mechanism to activate NRF2 target gene transcription [73], [74]. The evidence that oxidized phospho lipids induce the expression of target genes via Nrf2 is however very strong and corroborated by earlier studies using Nrf2 deficient cells [31,75].…”

The Expression of the Endogenous mTORC1 Inhibitor Sestrin 2 Is Induced by UVB and Balanced with the Expression Level of Sestrin 1

“…Fresh skin explants were placed in 6-well plates containing PBS and irradiated directly. As a light source for UVA, a Sellamed 3000-type solar simulator (Sellas Medizinische Geräte, Ennepetal, Germany) filtered for the emission of UVA (340–440 nm) was used [48]. Its spectrum is described in a previous study [49].…”

Stress-Induced EGFR Trafficking: Mechanisms, Functions, and Therapeutic Implications

“…Interestingly, both UV and cisplatin stimulate cytoprotective autophagy, which is a resistance mechanism for UV- or cisplatin-induced cell death [59–66]. This raises the important question: does endosomally accumulated EGFR mediate UV- or cisplatin-induced autophagy?…”