Induction of proteasomal activity in mammalian cells by lifespan-extending tRNA synthetase inhibitors.

ABSTRACT: We have recently shown that multiple tRNA synthetase inhibitors can greatly increase lifespan in multiple models by acting through the conserved transcription factor ATF4. Here, we show that these compounds, and several others of the same class, can greatly upregulate mammalian ATF4 in cells in vitro, in a dose dependent manner. Further, RNASeq analysis of these cells pointed toward changes in protein turnover. In subsequent experiments here we show that multiple tRNA synthetase inhibitors can greatly upregulate activity of the ubiquitin proteasome system (UPS) in cells in an ATF4-dependent manner. The UPS plays an important role in the turnover of many damaged or dysfunctional proteins in an organism. Increasing UPS activity has been shown to enhance the survival of Huntington's disease c

SUBMITTER: Mariner BL 

PROVIDER: S-EPMC10828360 | biostudies-literature | 2024 Apr

REPOSITORIES: biostudies-literature