Sterility-Independent Enhancement of Proteasome Function via Floxuridine-Triggered Detoxification in C. elegans

The ubiquitin-proteasome system (UPS) functionality is vital for proteostasis, contributing to stress resilience, lifespan, and thermal adaptability. In Caenorhabditis elegans, proteasome constituents such as the RPN-6 and PBS-6 subunits or the PSME-3 activator are respectively linked to heat resistance, survival at low temperatures (4{degrees}C), and longevity at moderate cold (15{degrees}C). Since the inhibition of germline stem cells proliferation is associated with robust proteostasis in worms, we utilized floxuridine (FUdR), a compound known for inducing sterility, to examine whether it could reinforce UPS under proteasome dysfunction, particularly to foster cold survival. We demonstrate that FUdR promotes proteasome resilience during its inhibition or subunit deficits, supporting normal lifespan and facilitating adaptation to cold. FUdRs elevation of the UPS activity occurs independently of main proteostasis regulators and is partly driven by SKN-1-regulated transcription, especially under reduced proteasome function. Additionally, we uncover a FUdR-stimulated detoxification pathway, distinct from both SKN-1 and the germline, with GST-24 emerging as a critical mediator of the UPS buffering. This research underscores FUdRs role in the UPS modulation and its contribution to survival of worms in low-temperature conditions. HIGHLIGHTSO_LIFloxuridine (FUdR) enhances ubiquitin-proteasome system activity in C. elegans, independent of primary proteostasis regulators. C_LIO_LIFUdR permits worms to maintain a normal lifespan and facilitates their adaptation to cold in the context of proteasome deficits. C_LIO_LIActing independently of the germline and SKN-1, FUdR triggers a detoxification pathway, with GST-24 as a pivotal component in modulating the ubiquitin-proteasome system. C_LI