Oxidative stress-dependent regulation of Forkhead box O4 activity by nemo-like kinase.
Forkhead box O (FOXO) transcription factors are involved in various cellular processes, including cell proliferation, stress resistance, metabolism, and longevity. Regulation of FOXO transcriptional activity occurs mainly through a variety of post-translational modifications, including phosphorylation, acetylation, and ubiquitination. Here we describe nemo-like kinase (NLK) as a novel regulator of FOXOs. NLK binds to and phosphorylates FOXO1, FOXO3a, and FOXO4 on multiple residues. NLK acts as a negative regulator of FOXO transcriptional activity. For FOXO4 we show that NLK-mediated loss of FOXO4 activity co-occurs with inhibition of FOXO4 monoubiquitination. Previously, we have shown that oxidative stress-induced monoubiquitination of FOXO4 stimulates its transactivation, which leads to activation of an antioxidant defensive program. Conversely, NLK-dependent inhibition of FOXO4 activity can provide a means to downregulate this defensive program, when oxidative stress reaches a level beyond which repair is no longer feasible and cells need to undergo apoptosis.
Szypowska
Anna A
AA
Laboratory of Physiological Chemistry, Department of Biomedical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.
de Ruiter
Hesther
H
Meijer
Lars A T
LA
Smits
Lydia M M
LM
Burgering
Boudewijn M T
BM
D000818:Animals; D018797:Cell Cycle Proteins; D051858:Forkhead Transcription Factors; D047468:Immunoprecipitation; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018384:Oxidative Stress / Q000235:genetics / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination
D018797:Cell Cycle Proteins; C108803:FOXO4 protein, human; D051858:Forkhead Transcription Factors; D047908:Intracellular Signaling Peptides and Proteins; D014157:Transcription Factors; C470551:NLK protein, human; D017346:Protein Serine-Threonine Kinases