FoxO1 Is a Novel Regulator of 20S Proteasome Subunits Expression and Activity
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...
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2021-02-01
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doaj-4c518bf1230e4fd586c29f4f97b177ae2021-02-05T06:16:11ZengFrontiers Media S.A.Frontiers in Cell and Developmental Biology2296-634X2021-02-01910.3389/fcell.2021.625715625715FoxO1 Is a Novel Regulator of 20S Proteasome Subunits Expression and ActivityMarianna Kapetanou0Tobias Nespital1Luke S. Tain2Andre Pahl3Linda Partridge4Efstathios S. Gonos5Laboratory of Molecular and Cellular Aging, Institute of Chemical Biology, National Hellenic Research Foundation, Athens, GreeceDepartment of Biological Mechanisms of Ageing, Max Planck Institute for Biology of Ageing, Cologne, GermanyDepartment of Biological Mechanisms of Ageing, Max Planck Institute for Biology of Ageing, Cologne, GermanyDepartment of Biological Mechanisms of Ageing, Max Planck Institute for Biology of Ageing, Cologne, GermanyDepartment of Biological Mechanisms of Ageing, Max Planck Institute for Biology of Ageing, Cologne, GermanyLaboratory of Molecular and Cellular Aging, Institute of Chemical Biology, National Hellenic Research Foundation, Athens, GreeceProteostasis 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.https://www.frontiersin.org/articles/10.3389/fcell.2021.625715/fullFOXO factorsinsulin signalingproteostasisproteasomeaginglongevity |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Marianna Kapetanou Tobias Nespital Luke S. Tain Andre Pahl Linda Partridge Efstathios S. Gonos |
spellingShingle |
Marianna Kapetanou Tobias Nespital Luke S. Tain Andre Pahl Linda Partridge Efstathios S. Gonos FoxO1 Is a Novel Regulator of 20S Proteasome Subunits Expression and Activity Frontiers in Cell and Developmental Biology FOXO factors insulin signaling proteostasis proteasome aging longevity |
author_facet |
Marianna Kapetanou Tobias Nespital Luke S. Tain Andre Pahl Linda Partridge Efstathios S. Gonos |
author_sort |
Marianna Kapetanou |
title |
FoxO1 Is a Novel Regulator of 20S Proteasome Subunits Expression and Activity |
title_short |
FoxO1 Is a Novel Regulator of 20S Proteasome Subunits Expression and Activity |
title_full |
FoxO1 Is a Novel Regulator of 20S Proteasome Subunits Expression and Activity |
title_fullStr |
FoxO1 Is a Novel Regulator of 20S Proteasome Subunits Expression and Activity |
title_full_unstemmed |
FoxO1 Is a Novel Regulator of 20S Proteasome Subunits Expression and Activity |
title_sort |
foxo1 is a novel regulator of 20s proteasome subunits expression and activity |
publisher |
Frontiers Media S.A. |
series |
Frontiers in Cell and Developmental Biology |
issn |
2296-634X |
publishDate |
2021-02-01 |
description |
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. |
topic |
FOXO factors insulin signaling proteostasis proteasome aging longevity |
url |
https://www.frontiersin.org/articles/10.3389/fcell.2021.625715/full |
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