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Adaptive homeostasis enables rapid cellular signaling, leading to transcriptional and translational modifications (Davies, 2016) [1]. The Proteasome is one of the main cellular proteolytic enzymes that plays an essential role in the rapid clearance of oxidatively damaged cellular proteins, and is highly responsive to oxidative stress. Upon exposure to even very low, signaling levels of oxidants, the predominant form of the Proteasome becomes the ATP-independent 20S proteasome that enables rapid clearance of damaged proteins. Subsequently there is also a concurrent upregulation of de novo 20S proteasome synthesis. These cellular adaptations not only ensure effective and efficient removal of damaged proteins, but prepare cells to better cope with future, more severe oxidative insults. Male and female Drosophila melanogaster fruit flies were pretreated with an adaptive amount of an oxidant (10 µM hydrogen peroxide or 0.5 µM paraquat) to assess the changes in proteolytic capacity and the role of the 20S proteasome. Additionally, the adaptive signaling by non-damaging amounts of hydrogen peroxide or paraquat) were used to assess changes in male and female fruit flies, following a subsequent more toxic amount of the two oxidants. Further analysis and detailed results about the adaptive role of the 20S proteasome in multiple D. melanogaster strains can be found in “Sexual Dimorphism in Oxidant-Induced Adaptive Homeostasis in Multiple Wild-Type D. melanogaster Strains” (Pomatto et al., 2018) [2]. Keywords: 20S proteasome, Sexual-dimorphism, Adaptive homeostasis, Proteolysis, D. melanogaster

The Nrf2 signal transduction pathway plays a major role in adaptive responses to oxidative stress and in maintaining adaptive homeostasis, yet Nrf2 signaling undergoes a significant age-dependent decline that is still poorly understood. We used mouse embryonic fibroblasts (MEFs) cultured under hyperoxic conditions of 40% O2, as a model of accelerated ageing. Hyperoxia increased baseline levels of Nrf2 and multiple transcriptional targets (20S Proteasome, Immunoproteasome, Lon protease, NQO1, and HO-1), but resulted in loss of cellular ability to adapt to signaling levels (1.0 μM) of H2O2. In contrast, MEFs cultured at physiologically relevant conditions of 5% O2 exhibited a transient induction of Nrf2 Phase II target genes and stress-protective enzymes (the Lon protease and OXR1) following H2O2 treatment. Importantly, all of these effects have been seen in older cells and organisms. Levels of Two major Nrf2 inhibitors, Bach1 and c-Myc, were strongly elevated by hyperoxia and appeared to exert a ceiling on Nrf2 signaling. Bach1 and c-Myc also increase during ageing and may thus be the mechanism by which adaptive homeostasis is compromised with age. Keywords: Adaptive homeostasis, Hyperoxia, Nrf2, 20S proteasome, Immunoproteasome, NQO1, Bach1, c-Myc, Lon protease, OXR1