FOXO4 transcriptional activity is regulated by monoubiquitination and USP7/HAUSP.
FOXO (Forkhead box O) transcription factors are important regulators of cellular metabolism, cell-cycle progression and cell death. FOXO activity is regulated by multiple post-translational modifications, including phosphorylation, acetylation and polyubiquitination. Here, we show that FOXO becomes monoubiquitinated in response to increased cellular oxidative stress, resulting in its re-localization to the nucleus and an increase in its transcriptional activity. Deubiquitination of FOXO requires the deubiquitinating enzyme USP7/HAUSP (herpesvirus-associated ubiquitin-specific protease), which interacts with and deubiquitinates FOXO in response to oxidative stress. Oxidative stress-induced ubiquitination and deubiquitination by USP7 do not influence FOXO protein half-life. However, USP7 does negatively regulate FOXO transcriptional activity towards endogenous promoters. Our results demonstrate a novel mechanism of FOXO regulation and indicate that USP7 has an important role in regulating FOXO-mediated stress responses.
van der Horst
Armando
A
Department of Physiological Chemistry, Centre for Biomedical Genetics, University Medical Center Utrecht, 3584 CG Utrecht, The Netherlands.
de Vries-Smits
Alida M M
AM
Brenkman
Arjan B
AB
van Triest
Miranda H
MH
van den Broek
Niels
N
Colland
Frédéric
F
Maurice
Madelon M
MM
Burgering
Boudewijn M T
BM
D000818:Animals; D018797:Cell Cycle Proteins; D002478:Cells, Cultured; D010450:Endopeptidases / Q000378:metabolism*; D051858:Forkhead Transcription Factors; D005786:Gene Expression Regulation / Q000502:physiology*; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D007668:Kidney / Q000378:metabolism; D008175:Lung Neoplasms / Q000378:metabolism; D051379:Mice; D041681:NIH 3T3 Cells; D016877:Oxidants / Q000494:pharmacology; D018384:Oxidative Stress; D011499:Protein Processing, Post-Translational; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic; D014162:Transfection; D025801:Ubiquitin / Q000378:metabolism*; D043222:Ubiquitin Thiolesterase; D000076084:Ubiquitin-Specific Peptidase 7; D064570:Ubiquitin-Specific Proteases
D018797:Cell Cycle Proteins; C108803:FOXO4 protein, human; D051858:Forkhead Transcription Factors; D016877:Oxidants; D012333:RNA, Messenger; D014157:Transcription Factors; D025801:Ubiquitin; D006861:Hydrogen Peroxide; D010450:Endopeptidases; C464569:USP7 protein, human; D043222:Ubiquitin Thiolesterase; D000076084:Ubiquitin-Specific Peptidase 7; D064570:Ubiquitin-Specific Proteases; C579190:Usp7 protein, mouse