# Floxuridine supports UPS independent of germline signaling and proteostasis regulators via involvement of detoxification in C. elegans

## TL;DR

Floxuridine helps worms survive cold temperatures by boosting a protein recycling system through a detoxification pathway, unrelated to reproduction or usual stress responses.

## Contribution

Floxuridine enhances UPS activity via detoxification, independent of germline signaling and proteostasis regulators.

## Key findings

- Floxuridine improves UPS activity and cold survival in C. elegans with proteasome dysfunction.
- Floxuridine's effect is independent of major proteostasis regulators and germ cell processes.
- Detoxification pathway involving GST-24 contributes to enhanced UPS activity.

## Abstract

The ubiquitin-proteasome system (UPS) is critical for maintaining proteostasis, influencing stress resilience, lifespan, and thermal adaptability in organisms. In Caenorhabditis elegans, specific proteasome subunits and activators, such as RPN-6, PBS-6, and PSME-3, are associated with heat resistance, survival at cold (4°C), and enhanced longevity at moderate temperatures (15°C). Previously linked to improving proteostasis, we investigated the impact of sterility-inducing floxuridine (FUdR) on UPS functionality under proteasome dysfunction and its potential to improve cold survival. Our findings reveal that FUdR significantly enhances UPS activity and resilience during proteasome inhibition or subunit deficiency, supporting worms’ normal lifespan and adaptation to cold. Importantly, FUdR effect on UPS activity occurs independently of major proteostasis regulators and does not rely on the germ cells proliferation or spermatogenesis. Instead, FUdR activates a distinct detoxification pathway that supports UPS function, with GST-24 appearing to be one of the factors contributing to the enhanced activity of the UPS upon knockdown of the SKN-1-mediated proteasome surveillance pathway. Our study highlights FUdR unique role in the UPS modulation and its crucial contribution to enhancing survival under low-temperature stress, providing new insights into its mechanisms of action and potential therapeutic applications.

In our study, we investigate the ubiquitin-proteasome system (UPS) in Caenorhabditis elegans, a crucial cellular machinery for degrading and recycling misfolded or excess proteins. The efficiency of this system is vital for cell health, particularly under stress conditions such as cold. We found that floxuridine (FUdR), commonly used to induce sterility in nematodes, also triggers an alternative UPS-stimulating or UPS-relieving pathway. This supports worms’ lifespan and ability to survive at low temperatures (4°C) despite proteasome deficiencies. This enhancement occurs independently of major proteostasis regulators and does not rely on reproductive pathways or conventional stress response mechanisms. Instead, FUdR activates a distinct detoxification pathway that can boost UPS activity, with GST-24 appearing to be one of the contributing factors. Our findings reveal a novel aspect of FUdR action, suggesting potential strategies for enhancing cellular resilience to environmental stress and aging in broader biological contexts.