The age- and sex-specific decline of the 20s proteasome and the Nrf2/CncC signal transduction pathway in adaption and resistance to oxidative stress in Drosophila melanogaster

Abstract

Hallmarks of aging include loss of protein homeostasis and dysregulation of stress-adaptive pathways. Loss of adaptive homeostasis, increases accumulation of DNA, protein, and lipid damage. During acute stress, the Cnc-C (Drosophila Nrf2 orthologue) transcriptionally-regulated 20S proteasome degrades damaged proteins in an ATP-independent manner. Exposure to very low, non-toxic, signaling concentrations of the redox-signaling agent hydrogen peroxide (H2O2) cause adaptive increases in the de novo expression and proteolytic activity/capacity of the 20S proteasome in female D. melanogaster (fruit-flies). Female 20S proteasome induction was accompanied by increased tolerance to a subsequent normally toxic but sub-lethal amount of H2O2, and blocking adaptive increases in proteasome expression also prevented full adaptation. We find, however, that this adaptive response is both sex- and age-dependent. Both increased proteasome expression and activity, and increased oxidative-stress resistance, in female flies, were lost with age. In contrast, male flies exhibited no H2O2 adaptation, irrespective of age. Furthermore, aging caused a generalized increase in basal 20S proteasome expression, but proteolytic activity and adaptation were both compromised. Finally, continual knockdown of Keep1 (the cytosolic inhibitor of Cnc-C) in adults resulted in older flies with greater stress resistance than their age-matched controls, but who still exhibited an age-associated loss of adaptive homeostasis.

Novel treatment strategies for chronic kidney disease: insights from the animal kingdom

“…Moreover, sulforaphane suppresses NRF2-mediated hepatic glucose production and attenuates exaggerated glucose intolerance by an order of magnitude similar to that of metformin in patients with type 2 diabetes mellitus (T2DM) (283). However, forced overexpression of NRF2 might not always be enough to restore adaptive responses (291). For example, the potent NRF2 agonist bardoxolone methyl increases the risk of heart failure compared with placebo in a clinical trial with patients with T2DM and stage 4 CKD (292), which highlights potential limitations of manipulating transcription factors.…”

Regulating resistance: CncC:Maf, antioxidant response elements and the overexpression of detoxification genes in insecticide resistance

“…Under normal conditions, Nrf2 is retained cytoplasmically, bound to the cytoskeletal ubiquitin ligase Keap1. Upon stress exposure, Nrf2 releases, translocates to the nucleus, and forms a heterodimer with a small Muscle Aponeurosis Fibromatosis (Maf-S) protein [6] binding to AREs upstream of a battery of antioxidant genes ( Figure 1) including GSTs [7][8][9], carboxylesterases [10], cytochromes p450 [11] and ABC transporters [12] and is involved in regulation of the proteasome, serving to degrade damaged proteins and enzymes following stress-induced damage [13]. In Drosophila the insect Nrf2 ortholog Cap collar isofor C, (CncC), is known to have a central role in both development and the stress response [5,14].…”

Redox regulation of proteasome function

“…Recently, this adaptive response has been revealed to be sex- and age-dependent in Drosophila melanogaster [61]. Nrf2/ Keap-1 axis was also shown to play a key role in stem cell differentiation where ROS levels are constantly altered.…”