이병훈 (DGIST (대구경북과학기술원))

한빛사논문

조회377

DGIST (대구경북과학기술원)

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Autophagy, Aug 08 2024, | https://doi.org/10.1080/15548627.2024.2389607 Pharmacological inhibition of USP14 delays proteostasis-associated aging in a proteasome-dependent but foxo-independent manner

Jin Ju Lim ^{1 †}, Sujin Noh ^{1 †}, Woojun Kang^{2 †}, Bom Hyun ¹, Byung-Hoon Lee ^{2 *}, Seogang Hyun ^{1 *}

¹Department of Life Science, Chung-Ang University, Seoul, Republic of Korea.

²Department of New Biology, Daegu-Gyeongbuk Institute of Science & Technology (DGIST), Daegu, Republic of Korea.

^†These authors contributed equally
^*Corresponding authors: correspondence to Byung-Hoon Lee or Seogang Hyun

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.

논문정보

형식Research article
게재일2024년 08월 (BRIC 등록일 2024-08-09)
연구진국내 연구진
분야 생명과학 > 노화/암생물학

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