The proteasome beta 5 subunit is essential for sexually divergent adaptive homeostatic responses to oxidative stress in D. melanogaster

Abstract

Our studies center on the physiological phenomenon of adaptive homeostasis in which very low, signaling levels of an oxidant can induce transient expansion of the baseline homeostatic range of protective mechanisms, resulting in transient stress protection. The 20S proteasome is a major element of such inducible defense enzymes against oxidative stress but the relative importance of each of its three proteolytic subunits, β1, β2, and β5, is only poorly understood. We focused the present studies on determining the role of the β5 subunit in adaptation, survival, and lifespan. Decreased expression of the 20S proteasome β5 subunit (with RNAi) blocked the adaptive increase in the catalytic activities of the 20S proteasome response to signaling levels of H₂O₂ in female flies. Similarly, female-specific adaptive increases in survival following H₂O₂ pretreatment and subsequent toxic challenge was blocked. In contrast, direct overexpression of the 20S proteasome β5 subunit enabled an increased 20S proteasome proteolytic response, but prevented further adaptive homeostatic increases through H₂O₂ signaling, indicating there is a maximum 'ceiling' to the adaptive response. Males showed no adaptive change in proteasomal levels or activity whatsoever with H₂O₂ pretreatment and exhibited no significant impact upon the other 2 proteolytic subunits of the proteasome. However, chronic loss of the β5 subunit led to shortened lifespan in both sexes. Our exploration of the importance of the 20S proteasome β5 subunit in adaptive homeostasis highlights the interconnection between signal transduction pathways and regulated gene expression in sexually divergent responses to oxidative stimulation.