Pharmacological inhibition of USP14 delays proteostasis-associated aging in a proteasome-dependent but foxo-independent manner

ABSTRACT

Aging is often accompanied by a decline in proteostasis, manifested as an increased propensity for misfolded protein aggregates, which are prevented by protein quality control systems, such as the ubiquitin-proteasome system (UPS) and macroautophagy/autophagy. Although the role of the UPS and autophagy in slowing age-induced proteostasis decline has been elucidated, limited information is available on how these pathways can be activated in a collaborative manner to delay proteostasis-associated aging. Here, we show that activation of the UPS via the pharmacological inhibition of USP14 (ubiquitin specific peptidase 14) using IU1 improves proteostasis and autophagy decline caused by aging or proteostatic stress in Drosophila and human cells. Treatment with IU1 not only alleviated the aggregation of polyubiquitinated proteins in aging Drosophila flight muscles but also extended the fly lifespan with enhanced locomotive activity via simultaneous activation of the UPS and autophagy. Interestingly, the effect of this drug disappeared when proteasomal activity was inhibited, but was evident upon proteostasis disruption by foxo mutation. Overall, our findings shed light on potential strategies to efficiently ameliorate age-associated pathologies associated with perturbed proteostasis.

KEYWORDS:

• Autophagy
• foxo
• IU1
• proteostasis
• ubiquitin-proteasome system
• ubiquitin-specific peptidase 14

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Acknowledgements

We thank the Bloomington Drosophila Stock Center (University of Indiana, Bloomington, IL, USA) for providing the fly stock used in this study. We also thank C. Kang (Seoul National University) and D. Cho (Kyungpook National University) for providing the immortalized fibroblasts and mCherry-pHluorin-LC3 reporter, respectively.

Disclosure statement

No potential conflict of interest was reported by the authors

Data availability statement

All study data are included in the manuscript and its Supplementary Material files.

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/15548627.2024.2389607.

Additional information

Funding

This research was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF), funded by the Ministry of Education, Science, and Technology (Grant Number: 2023R1A2C1005908 to S.H.), NRF grants from the Ministry of Science and ICT (Grant numbers: 2022R1A4A2000703 2022R1A2C1092638 to B.-H.L.), and DGIST R&D Programs (Grant Numbers: 24-CoE-BT-01 & 24-HRHR±04 to B.-H.L.).