The proteasome is a complex structure in the cell that is responsible for breaking down unwanted proteins. Like other recycling processes, proteasomal function is connected to life span in short-lived species. Better cell maintenance in response to stress and damage improves cell function, organ function, and longevity. The proteasome is made up of many different proteins, produced in the cell at difference rates. The least produced proteins are rate-limiting for proteasomal activity, and researchers have shown that boosting production of some of the proteasome subunit proteins can improve proteasomal function and increase life span in flies and nematodes. In the work here, researchers suggest that the transcription factor FOXO1, known to influence life span, works at least in part through this mechanism: it may either influence proteasomal function by determining the number of subunit protein molecules that are available for use in the cell.
Proteostasis collapses during aging resulting, among other things, in the accumulation of damaged and aggregated proteins. The proteasome is the main cellular proteolytic system and plays a fundamental role in the maintenance of protein homeostasis. Our previous work has demonstrated that senescence and aging are related to a decline in proteasome content and activities, while its activation extends lifespan in vitro and in vivo in various species. In addition, pharmacological or genetic induction of the proteasome alleviates the pathological phenotype of protein aggregation-related diseases, such as Alzheimer's disease. Here, we demonstrate that the Forkhead box-O1 (FoxO1) transcription factor directly regulates the expression of the 20S proteasome catalytic subunit β5 and, hence, proteasome activity.
The 20S core proteasome has barrel-like configuration and is comprised by seven different α subunits and seven distinct β subunits. Three β subunits, namely β1, β2, and β5, possess proteolytic activities with different substrate specificities. We have shown that human mesenchymal stem cells (hMSCs) exhibit a senescence-related decline of proteasome content and aberrations in physiological assembly of proteasome complexes during prolonged in vitro expansion, while proteasome activation via overexpression of the catalytic β5 subunit can enhance their stemness and lifespan.
We demonstrate that knockout of FoxO1, but not of FoxO3, in mice severely impairs proteasome activity in several tissues, while depletion of IRS1 enhances proteasome function. Importantly, we show that FoxO1 directly binds on the promoter region of the rate-limiting catalytic β5 proteasome subunit to regulate its expression. In summary, this study reveals the direct role of FoxO factors in the regulation of proteasome function and provides new insight into how FoxOs affect proteostasis and, in turn, longevity.