FoxO1 Is a Novel Regulator of 20S Proteasome Subunits Expression and Activity.

Autor:	Kapetanou M; Laboratory of Molecular and Cellular Aging, Institute of Chemical Biology, National Hellenic Research Foundation, Athens, Greece., Nespital T; Department of Biological Mechanisms of Ageing, Max Planck Institute for Biology of Ageing, Cologne, Germany., Tain LS; Department of Biological Mechanisms of Ageing, Max Planck Institute for Biology of Ageing, Cologne, Germany., Pahl A; Department of Biological Mechanisms of Ageing, Max Planck Institute for Biology of Ageing, Cologne, Germany., Partridge L; Department of Biological Mechanisms of Ageing, Max Planck Institute for Biology of Ageing, Cologne, Germany., Gonos ES; Laboratory of Molecular and Cellular Aging, Institute of Chemical Biology, National Hellenic Research Foundation, Athens, Greece.
Jazyk:	angličtina
Zdroj:	Frontiers in cell and developmental biology [Front Cell Dev Biol] 2021 Feb 05; Vol. 9, pp. 625715. Date of Electronic Publication: 2021 Feb 05 (Print Publication: 2021).
DOI:	10.3389/fcell.2021.625715
Abstrakt:	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. However, the mechanisms underlying this age-related decline of proteasome function and the down-regulation in expression of its subunits remain largely unclear. Here, we demonstrate that the Forkhead box-O1 (FoxO1) transcription factor directly regulates the expression of a 20S proteasome catalytic subunit and, hence, proteasome activity. Specifically, 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. Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. (Copyright © 2021 Kapetanou, Nespital, Tain, Pahl, Partridge and Gonos.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu